Substances that are recognized by the immune system and induce an immune reaction.
Substances elaborated by bacteria that have antigenic activity.
Proteins, glycoprotein, or lipoprotein moieties on surfaces of tumor cells that are usually identified by monoclonal antibodies. Many of these are of either embryonic or viral origin.
Antigens on surfaces of cells, including infectious or foreign cells or viruses. They are usually protein-containing groups on cell membranes or walls and may be isolated.
Substances elaborated by viruses that have antigenic activity.
Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens (ANTIGENS, CD3). Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta (RECEPTORS, ANTIGEN, T-CELL, ALPHA-BETA) or gamma-delta (RECEPTORS, ANTIGEN, T-CELL, GAMMA-DELTA) chains.
A classification of T-lymphocytes, especially into helper/inducer, suppressor/effector, and cytotoxic subsets, based on structurally or functionally different populations of cells.
Differentiation antigens residing on mammalian leukocytes. CD stands for cluster of differentiation, which refers to groups of monoclonal antibodies that show similar reactivity with certain subpopulations of antigens of a particular lineage or differentiation stage. The subpopulations of antigens are also known by the same CD designation.
A critical subpopulation of T-lymphocytes involved in the induction of most immunological functions. The HIV virus has selective tropism for the T4 cell which expresses the CD4 phenotypic marker, a receptor for HIV. In fact, the key element in the profound immunosuppression seen in HIV infection is the depletion of this subset of T-lymphocytes.
Any part or derivative of any protozoan that elicits immunity; malaria (Plasmodium) and trypanosome antigens are presently the most frequently encountered.
The major group of transplantation antigens in the mouse.
The major interferon produced by mitogenically or antigenically stimulated LYMPHOCYTES. It is structurally different from TYPE I INTERFERON and its major activity is immunoregulation. It has been implicated in the expression of CLASS II HISTOCOMPATIBILITY ANTIGENS in cells that do not normally produce them, leading to AUTOIMMUNE DISEASES.
The altered state of immunologic responsiveness resulting from initial contact with antigen, which enables the individual to produce antibodies more rapidly and in greater quantity in response to secondary antigenic stimulus.
Antigens determined by leukocyte loci found on chromosome 6, the major histocompatibility loci in humans. They are polypeptides or glycoproteins found on most nucleated cells and platelets, determine tissue types for transplantation, and are associated with certain diseases.
Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake.
Antibodies produced by a single clone of cells.
A critical subpopulation of regulatory T-lymphocytes involved in MHC Class I-restricted interactions. They include both cytotoxic T-lymphocytes (T-LYMPHOCYTES, CYTOTOXIC) and CD8+ suppressor T-lymphocytes.
Large, transmembrane, non-covalently linked glycoproteins (alpha and beta). Both chains can be polymorphic although there is more structural variation in the beta chains. The class II antigens in humans are called HLA-D ANTIGENS and are coded by a gene on chromosome 6. In mice, two genes named IA and IE on chromosome 17 code for the H-2 antigens. The antigens are found on B-lymphocytes, macrophages, epidermal cells, and sperm and are thought to mediate the competence of and cellular cooperation in the immune response. The term IA antigens used to refer only to the proteins encoded by the IA genes in the mouse, but is now used as a generic term for any class II histocompatibility antigen.
Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN.
CD4-positive T cells that inhibit immunopathology or autoimmune disease in vivo. They inhibit the immune response by influencing the activity of other cell types. Regulatory T-cells include naturally occurring CD4+CD25+ cells, IL-10 secreting Tr1 cells, and Th3 cells.
T-cell receptors composed of CD3-associated alpha and beta polypeptide chains and expressed primarily in CD4+ or CD8+ T-cells. Unlike immunoglobulins, the alpha-beta T-cell receptors recognize antigens only when presented in association with major histocompatibility (MHC) molecules.
Polyomavirus antigens which cause infection and cellular transformation. The large T antigen is necessary for the initiation of viral DNA synthesis, repression of transcription of the early region and is responsible in conjunction with the middle T antigen for the transformation of primary cells. Small T antigen is necessary for the completion of the productive infection cycle.
55-kDa antigens found on HELPER-INDUCER T-LYMPHOCYTES and on a variety of other immune cell types. CD4 antigens are members of the immunoglobulin supergene family and are implicated as associative recognition elements in MAJOR HISTOCOMPATIBILITY COMPLEX class II-restricted immune responses. On T-lymphocytes they define the helper/inducer subset. CD4 antigens also serve as INTERLEUKIN-15 receptors and bind to the HIV receptors, binding directly to the HIV ENVELOPE PROTEIN GP120.
Antigenic determinants recognized and bound by the T-cell receptor. Epitopes recognized by the T-cell receptor are often located in the inner, unexposed side of the antigen, and become accessible to the T-cell receptors after proteolytic processing of the antigen.
A soluble substance elaborated by antigen- or mitogen-stimulated T-LYMPHOCYTES which induces DNA synthesis in naive lymphocytes.
Specialized cells of the hematopoietic system that have branch-like extensions. They are found throughout the lymphatic system, and in non-lymphoid tissues such as SKIN and the epithelia of the intestinal, respiratory, and reproductive tracts. They trap and process ANTIGENS, and present them to T-CELLS, thereby stimulating CELL-MEDIATED IMMUNITY. They are different from the non-hematopoietic FOLLICULAR DENDRITIC CELLS, which have a similar morphology and immune system function, but with respect to humoral immunity (ANTIBODY PRODUCTION).
An encapsulated lymphatic organ through which venous blood filters.
Substances of fungal origin that have antigenic activity.
Sites on an antigen that interact with specific antibodies.
A subclass of HLA-D antigens that consist of alpha and beta chains. The inheritance of HLA-DR antigens differs from that of the HLA-DQ ANTIGENS and HLA-DP ANTIGENS.
Morphologic alteration of small B LYMPHOCYTES or T LYMPHOCYTES in culture into large blast-like cells able to synthesize DNA and RNA and to divide mitotically. It is induced by INTERLEUKINS; MITOGENS such as PHYTOHEMAGGLUTININS, and by specific ANTIGENS. It may also occur in vivo as in GRAFT REJECTION.
High-molecular weight glycoproteins uniquely expressed on the surface of LEUKOCYTES and their hemopoietic progenitors. They contain a cytoplasmic protein tyrosine phosphatase activity which plays a role in intracellular signaling from the CELL SURFACE RECEPTORS. The CD45 antigens occur as multiple isoforms that result from alternative mRNA splicing and differential usage of three exons.
Any part or derivative of a helminth that elicits an immune reaction. The most commonly seen helminth antigens are those of the schistosomes.
Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation.
A group of antigens that includes both the major and minor histocompatibility antigens. The former are genetically determined by the major histocompatibility complex. They determine tissue type for transplantation and cause allograft rejections. The latter are systems of allelic alloantigens that can cause weak transplant rejection.
Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.
A group of genetically identical cells all descended from a single common ancestral cell by mitosis in eukaryotes or by binary fission in prokaryotes. Clone cells also include populations of recombinant DNA molecules all carrying the same inserted sequence. (From King & Stansfield, Dictionary of Genetics, 4th ed)
A single, unpaired primary lymphoid organ situated in the MEDIASTINUM, extending superiorly into the neck to the lower edge of the THYROID GLAND and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat.
Form of passive immunization where previously sensitized immunologic agents (cells or serum) are transferred to non-immune recipients. When transfer of cells is used as a therapy for the treatment of neoplasms, it is called adoptive immunotherapy (IMMUNOTHERAPY, ADOPTIVE).
Immunized T-lymphocytes which can directly destroy appropriate target cells. These cytotoxic lymphocytes may be generated in vitro in mixed lymphocyte cultures (MLC), in vivo during a graft-versus-host (GVH) reaction, or after immunization with an allograft, tumor cell or virally transformed or chemically modified target cell. The lytic phenomenon is sometimes referred to as cell-mediated lympholysis (CML). These CD8-positive cells are distinct from NATURAL KILLER CELLS and NATURAL KILLER T-CELLS. There are two effector phenotypes: TC1 and TC2.
Costimulatory T-LYMPHOCYTE receptors that have specificity for CD80 ANTIGEN and CD86 ANTIGEN. Activation of this receptor results in increased T-cell proliferation, cytokine production and promotion of T-cell survival.
The specific failure of a normally responsive individual to make an immune response to a known antigen. It results from previous contact with the antigen by an immunologically immature individual (fetus or neonate) or by an adult exposed to extreme high-dose or low-dose antigen, or by exposure to radiation, antimetabolites, antilymphocytic serum, etc.
Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner.
Strains of mice in which certain GENES of their GENOMES have been disrupted, or "knocked-out". To produce knockouts, using RECOMBINANT DNA technology, the normal DNA sequence of the gene being studied is altered to prevent synthesis of a normal gene product. Cloned cells in which this DNA alteration is successful are then injected into mouse EMBRYOS to produce chimeric mice. The chimeric mice are then bred to yield a strain in which all the cells of the mouse contain the disrupted gene. Knockout mice are used as EXPERIMENTAL ANIMAL MODELS for diseases (DISEASE MODELS, ANIMAL) and to clarify the functions of the genes.
T-cell receptors composed of CD3-associated gamma and delta polypeptide chains and expressed primarily in CD4-/CD8- T-cells. The receptors appear to be preferentially located in epithelial sites and probably play a role in the recognition of bacterial antigens. The T-cell receptor gamma/delta chains are separate and not related to the gamma and delta chains which are subunits of CD3 (see ANTIGENS, CD3).
A specific HLA-A surface antigen subtype. Members of this subtype contain alpha chains that are encoded by the HLA-A*02 allele family.
A glycoprotein that is secreted into the luminal surface of the epithelia in the gastrointestinal tract. It is found in the feces and pancreaticobiliary secretions and is used to monitor the response to colon cancer treatment.
The phenomenon of target cell destruction by immunologically active effector cells. It may be brought about directly by sensitized T-lymphocytes or by lymphoid or myeloid "killer" cells, or it may be mediated by cytotoxic antibody, cytotoxic factor released by lymphoid cells, or complement.
Those proteins recognized by antibodies from serum of animals bearing tumors induced by viruses; these proteins are presumably coded for by the nucleic acids of the same viruses that caused the neoplastic transformation.
Membrane glycoproteins consisting of an alpha subunit and a BETA 2-MICROGLOBULIN beta subunit. In humans, highly polymorphic genes on CHROMOSOME 6 encode the alpha subunits of class I antigens and play an important role in determining the serological specificity of the surface antigen. Class I antigens are found on most nucleated cells and are generally detected by their reactivity with alloantisera. These antigens are recognized during GRAFT REJECTION and restrict cell-mediated lysis of virus-infected cells.
Established cell cultures that have the potential to propagate indefinitely.
The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.
An albumin obtained from the white of eggs. It is a member of the serpin superfamily.
An immunoassay utilizing an antibody labeled with an enzyme marker such as horseradish peroxidase. While either the enzyme or the antibody is bound to an immunosorbent substrate, they both retain their biologic activity; the change in enzyme activity as a result of the enzyme-antibody-antigen reaction is proportional to the concentration of the antigen and can be measured spectrophotometrically or with the naked eye. Many variations of the method have been developed.
Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs.
A costimulatory ligand expressed by ANTIGEN-PRESENTING CELLS that binds to CTLA-4 ANTIGEN with high specificity and to CD28 ANTIGEN with low specificity. The interaction of CD80 with CD28 ANTIGEN provides a costimulatory signal to T-LYMPHOCYTES, while its interaction with CTLA-4 ANTIGEN may play a role in inducing PERIPHERAL TOLERANCE.
The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of IgG, for example, IgG1, IgG2A, and IgG2B.
Antigens expressed primarily on the membranes of living cells during sequential stages of maturation and differentiation. As immunologic markers they have high organ and tissue specificity and are useful as probes in studies of normal cell development as well as neoplastic transformation.
IMMUNOGLOBULINS on the surface of B-LYMPHOCYTES. Their MESSENGER RNA contains an EXON with a membrane spanning sequence, producing immunoglobulins in the form of type I transmembrane proteins as opposed to secreted immunoglobulins (ANTIBODIES) which do not contain the membrane spanning segment.
Endogenous tissue constituents that have the ability to interact with AUTOANTIBODIES and cause an immune response.
Deliberate stimulation of the host's immune response. ACTIVE IMMUNIZATION involves administration of ANTIGENS or IMMUNOLOGIC ADJUVANTS. PASSIVE IMMUNIZATION involves administration of IMMUNE SERA or LYMPHOCYTES or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow).
They are oval or bean shaped bodies (1 - 30 mm in diameter) located along the lymphatic system.
Manifestations of the immune response which are mediated by antigen-sensitized T-lymphocytes via lymphokines or direct cytotoxicity. This takes place in the absence of circulating antibody or where antibody plays a subordinate role.
Subpopulation of CD4+ lymphocytes that cooperate with other lymphocytes (either T or B) to initiate a variety of immune functions. For example, helper-inducer T-cells cooperate with B-cells to produce antibodies to thymus-dependent antigens and with other subpopulations of T-cells to initiate a variety of cell-mediated immune functions.
Nuclear antigen with a role in DNA synthesis, DNA repair, and cell cycle progression. PCNA is required for the coordinated synthesis of both leading and lagging strands at the replication fork during DNA replication. PCNA expression correlates with the proliferation activity of several malignant and non-malignant cell types.
Glycoproteins found on the membrane or surface of cells.
Polymorphic class I human histocompatibility (HLA) surface antigens present on almost all nucleated cells. At least 20 antigens have been identified which are encoded by the A locus of multiple alleles on chromosome 6. They serve as targets for T-cell cytolytic responses and are involved with acceptance or rejection of tissue/organ grafts.
Serological reactions in which an antiserum against one antigen reacts with a non-identical but closely related antigen.
The number of LYMPHOCYTES per unit volume of BLOOD.
A CELL LINE derived from human T-CELL LEUKEMIA and used to determine the mechanism of differential susceptibility to anti-cancer drugs and radiation.
An inhibitory T CELL receptor that is closely related to CD28 ANTIGEN. It has specificity for CD80 ANTIGEN and CD86 ANTIGEN and acts as a negative regulator of peripheral T cell function. CTLA-4 antigen is believed to play role in inducing PERIPHERAL TOLERANCE.
Subset of helper-inducer T-lymphocytes which synthesize and secrete interleukin-2, gamma-interferon, and interleukin-12. Due to their ability to kill antigen-presenting cells and their lymphokine-mediated effector activity, Th1 cells are associated with vigorous delayed-type hypersensitivity reactions.
The production of ANTIBODIES by proliferating and differentiated B-LYMPHOCYTES under stimulation by ANTIGENS.
A glycoprotein that is a kallikrein-like serine proteinase and an esterase, produced by epithelial cells of both normal and malignant prostate tissue. It is an important marker for the diagnosis of prostate cancer.
A subclass of winged helix DNA-binding proteins that share homology with their founding member fork head protein, Drosophila.
The lipopolysaccharide-protein somatic antigens, usually from gram-negative bacteria, important in the serological classification of enteric bacilli. The O-specific chains determine the specificity of the O antigens of a given serotype. O antigens are the immunodominant part of the lipopolysaccharide molecule in the intact bacterial cell. (From Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed)
The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.
Receptors present on activated T-LYMPHOCYTES and B-LYMPHOCYTES that are specific for INTERLEUKIN-2 and play an important role in LYMPHOCYTE ACTIVATION. They are heterotrimeric proteins consisting of the INTERLEUKIN-2 RECEPTOR ALPHA SUBUNIT, the INTERLEUKIN-2 RECEPTOR BETA SUBUNIT, and the INTERLEUKIN RECEPTOR COMMON GAMMA-CHAIN.
All of the processes involved in increasing CELL NUMBER including CELL DIVISION.
Antigens expressed on the cell membrane of T-lymphocytes during differentiation, activation, and normal and neoplastic transformation. Their phenotypic characterization is important in differential diagnosis and studies of thymic ontogeny and T-cell function.
A trisaccharide antigen expressed on glycolipids and many cell-surface glycoproteins. In the blood the antigen is found on the surface of NEUTROPHILS; EOSINOPHILS; and MONOCYTES. In addition, CD15 antigen is a stage-specific embryonic antigen.
A soluble factor produced by activated T-LYMPHOCYTES that induces the expression of MHC CLASS II GENES and FC RECEPTORS on B-LYMPHOCYTES and causes their proliferation and differentiation. It also acts on T-lymphocytes, MAST CELLS, and several other hematopoietic lineage cells.
Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.
Antigens that exist in alternative (allelic) forms in a single species. When an isoantigen is encountered by species members who lack it, an immune response is induced. Typical isoantigens are the BLOOD GROUP ANTIGENS.
Genetically identical individuals developed from brother and sister matings which have been carried out for twenty or more generations, or by parent x offspring matings carried out with certain restrictions. All animals within an inbred strain trace back to a common ancestor in the twentieth generation.
Carbohydrate antigens expressed by malignant tissue. They are useful as tumor markers and are measured in the serum by means of a radioimmunoassay employing monoclonal antibodies.
The property of antibodies which enables them to react with some ANTIGENIC DETERMINANTS and not with others. Specificity is dependent on chemical composition, physical forces, and molecular structure at the binding site.
A member of the tumor necrosis factor receptor superfamily with specificity for CD40 LIGAND. It is found on mature B-LYMPHOCYTES and some EPITHELIAL CELLS, lymphoid DENDRITIC CELLS. Evidence suggests that CD40-dependent activation of B-cells is important for generation of memory B-cells within the germinal centers. Mutations of the gene for CD40 antigen result in HYPER-IGM IMMUNODEFICIENCY SYNDROME, TYPE 3. Signaling of the receptor occurs through its association with TNF RECEPTOR-ASSOCIATED FACTORS.
A low affinity interleukin-2 receptor subunit that combines with the INTERLEUKIN-2 RECEPTOR BETA SUBUNIT and the INTERLEUKIN RECEPTOR COMMON GAMMA-CHAIN to form a high affinity receptor for INTERLEUKIN-2.
A costimulatory ligand expressed by ANTIGEN-PRESENTING CELLS that binds to CD28 ANTIGEN with high specificity and to CTLA-4 ANTIGEN with low specificity. The interaction of CD86 with CD28 ANTIGEN provides a stimulatory signal to T-LYMPHOCYTES, while its interaction with CTLA-4 ANTIGEN may play a role in inducing PERIPHERAL TOLERANCE.
Subset of helper-inducer T-lymphocytes which synthesize and secrete the interleukins IL-4, IL-5, IL-6, and IL-10. These cytokines influence B-cell development and antibody production as well as augmenting humoral responses.
The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) TRANSPLANTATION ANTIGENS, genes which control the structure of the IMMUNE RESPONSE-ASSOCIATED ANTIGENS, HUMAN; the IMMUNE RESPONSE GENES which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement.
Differentiation antigens found on thymocytes and on cytotoxic and suppressor T-lymphocytes. CD8 antigens are members of the immunoglobulin supergene family and are associative recognition elements in MHC (Major Histocompatibility Complex) Class I-restricted interactions.
Lymphocytes responsible for cell-mediated immunity. Two types have been identified - cytotoxic (T-LYMPHOCYTES, CYTOTOXIC) and helper T-lymphocytes (T-LYMPHOCYTES, HELPER-INDUCER). They are formed when lymphocytes circulate through the THYMUS GLAND and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen.
Molecules on the surface of B- and T-lymphocytes that recognize and combine with specific antigens.
Members of the class of compounds composed of AMINO ACIDS joined together by peptide bonds between adjacent amino acids into linear, branched or cyclical structures. OLIGOPEPTIDES are composed of approximately 2-12 amino acids. Polypeptides are composed of approximately 13 or more amino acids. PROTEINS are linear polypeptides that are normally synthesized on RIBOSOMES.
Cells artificially created by fusion of activated lymphocytes with neoplastic cells. The resulting hybrid cells are cloned and produce pure MONOCLONAL ANTIBODIES or T-cell products, identical to those produced by the immunologically competent parent cell.
Test for tissue antigen using either a direct method, by conjugation of antibody with fluorescent dye (FLUORESCENT ANTIBODY TECHNIQUE, DIRECT) or an indirect method, by formation of antigen-antibody complex which is then labeled with fluorescein-conjugated anti-immunoglobulin antibody (FLUORESCENT ANTIBODY TECHNIQUE, INDIRECT). The tissue is then examined by fluorescence microscopy.
A melanosome-specific protein that plays a role in the expression, stability, trafficking, and processing of GP100 MELANOMA ANTIGEN, which is critical to the formation of Stage II MELANOSOMES. The protein is used as an antigen marker for MELANOMA cells.
A tumor necrosis factor receptor subtype found in a variety of tissues and on activated LYMPHOCYTES. It has specificity for FAS LIGAND and plays a role in regulation of peripheral immune responses and APOPTOSIS. Multiple isoforms of the protein exist due to multiple ALTERNATIVE SPLICING. The activated receptor signals via a conserved death domain that associates with specific TNF RECEPTOR-ASSOCIATED FACTORS in the CYTOPLASM.
Partial proteins formed by partial hydrolysis of complete proteins or generated through PROTEIN ENGINEERING techniques.
The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.
Those hepatitis B antigens found on the surface of the Dane particle and on the 20 nm spherical and tubular particles. Several subspecificities of the surface antigen are known. These were formerly called the Australia antigen.
Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by AUTOIMMUNE DISEASES.
A member of the tumor necrosis factor receptor superfamily found on most T-LYMPHOCYTES. Activation of the receptor by CD70 ANTIGEN results in the increased proliferation of CD4-POSITIVE T-LYMPHOCYTES and CD8-POSITIVE T-LYMPHOCYTES. Signaling by the activated receptor occurs through its association with TNF RECEPTOR-ASSOCIATED FACTORS.
The fission of a CELL. It includes CYTOKINESIS, when the CYTOPLASM of a cell is divided, and CELL NUCLEUS DIVISION.
Subunits of the antigenic determinant that are most easily recognized by the immune system and thus most influence the specificity of the induced antibody.
Sets of cell surface antigens located on BLOOD CELLS. They are usually membrane GLYCOPROTEINS or GLYCOLIPIDS that are antigenically distinguished by their carbohydrate moieties.
A technique of culturing mixed cell types in vitro to allow their synergistic or antagonistic interactions, such as on CELL DIFFERENTIATION or APOPTOSIS. Coculture can be of different types of cells, tissues, or organs from normal or disease states.
Immunosuppression by reduction of circulating lymphocytes or by T-cell depletion of bone marrow. The former may be accomplished in vivo by thoracic duct drainage or administration of antilymphocyte serum. The latter is performed ex vivo on bone marrow before its transplantation.
Serum that contains antibodies. It is obtained from an animal that has been immunized either by ANTIGEN injection or infection with microorganisms containing the antigen.
A specific immune response elicited by a specific dose of an immunologically active substance or cell in an organism, tissue, or cell.
Glycoprotein members of the immunoglobulin superfamily which participate in T-cell adhesion and activation. They are expressed on most peripheral T-lymphocytes, natural killer cells, and thymocytes, and function as co-receptors or accessory molecules in the T-cell receptor complex.
Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the ANTIGEN (or a very similar shape) that induced their synthesis in cells of the lymphoid series (especially PLASMA CELLS).
Complex of at least five membrane-bound polypeptides in mature T-lymphocytes that are non-covalently associated with one another and with the T-cell receptor (RECEPTORS, ANTIGEN, T-CELL). The CD3 complex includes the gamma, delta, epsilon, zeta, and eta chains (subunits). When antigen binds to the T-cell receptor, the CD3 complex transduces the activating signals to the cytoplasm of the T-cell. The CD3 gamma and delta chains (subunits) are separate from and not related to the gamma/delta chains of the T-cell receptor (RECEPTORS, ANTIGEN, T-CELL, GAMMA-DELTA).
T-cell enhancement of the B-cell response to thymic-dependent antigens.
Substances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (Freund's adjuvant, BCG, Corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity.
The processes triggered by interactions of ANTIBODIES with their ANTIGENS.
Theoretical representations that simulate the behavior or activity of immune system, processes, or phenomena. They include the use of mathematical equations, computers, and other electrical equipment.
Bone marrow-derived lymphocytes that possess cytotoxic properties, classically directed against transformed and virus-infected cells. Unlike T CELLS; and B CELLS; NK CELLS are not antigen specific. The cytotoxicity of natural killer cells is determined by the collective signaling of an array of inhibitory and stimulatory CELL SURFACE RECEPTORS. A subset of T-LYMPHOCYTES referred to as NATURAL KILLER T CELLS shares some of the properties of this cell type.
A sex-specific cell surface antigen produced by the sex-determining gene of the Y chromosome in mammals. It causes syngeneic grafts from males to females to be rejected and interacts with somatic elements of the embryologic undifferentiated gonad to produce testicular organogenesis.
Class I human histocompatibility (HLA) surface antigens encoded by more than 30 detectable alleles on locus B of the HLA complex, the most polymorphic of all the HLA specificities. Several of these antigens (e.g., HLA-B27, -B7, -B8) are strongly associated with predisposition to rheumatoid and other autoimmune disorders. Like other class I HLA determinants, they are involved in the cellular immune reactivity of cytolytic T lymphocytes.
The demonstration of the cytotoxic effect on a target cell of a lymphocyte, a mediator released by a sensitized lymphocyte, an antibody, or complement.
The property of the T-CELL RECEPTOR which enables it to react with some antigens and not others. The specificity is derived from the structure of the receptor's variable region which has the ability to recognize certain antigens in conjunction with the MAJOR HISTOCOMPATIBILITY COMPLEX molecule.
A cytokine produced by a variety of cell types, including T-LYMPHOCYTES; MONOCYTES; DENDRITIC CELLS; and EPITHELIAL CELLS that exerts a variety of effects on immunoregulation and INFLAMMATION. Interleukin-10 combines with itself to form a homodimeric molecule that is the biologically active form of the protein.
Form of adoptive transfer where cells with antitumor activity are transferred to the tumor-bearing host in order to mediate tumor regression. The lymphoid cells commonly used are lymphokine-activated killer (LAK) cells and tumor-infiltrating lymphocytes (TIL). This is usually considered a form of passive immunotherapy. (From DeVita, et al., Cancer, 1993, pp.305-7, 314)
The outward appearance of the individual. It is the product of interactions between genes, and between the GENOTYPE and the environment.
Immunoglobulins produced in a response to BACTERIAL ANTIGENS.
White blood cells formed in the body's lymphoid tissue. The nucleus is round or ovoid with coarse, irregularly clumped chromatin while the cytoplasm is typically pale blue with azurophilic (if any) granules. Most lymphocytes can be classified as either T or B (with subpopulations of each), or NATURAL KILLER CELLS.
Human immune-response or Class II antigens found mainly, but not exclusively, on B-lymphocytes and produced from genes of the HLA-D locus. They are extremely polymorphic families of glycopeptides, each consisting of two chains, alpha and beta. This group of antigens includes the -DR, -DQ and -DP designations, of which HLA-DR is most studied; some of these glycoproteins are associated with certain diseases, possibly of immune etiology.
Functional inactivation of T- or B-lymphocytes rendering them incapable of eliciting an immune response to antigen. This occurs through different mechanisms in the two kinds of lymphocytes and can contribute to SELF TOLERANCE.
Antigens of the virion of the HEPATITIS B VIRUS or the Dane particle, its surface (HEPATITIS B SURFACE ANTIGENS), core (HEPATITIS B CORE ANTIGENS), and other associated antigens, including the HEPATITIS B E ANTIGENS.
Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation.
Proteins prepared by recombinant DNA technology.
Vaccines or candidate vaccines designed to prevent or treat cancer. Vaccines are produced using the patient's own whole tumor cells as the source of antigens, or using tumor-specific antigens, often recombinantly produced.
Differentiation antigens expressed on B-lymphocytes and B-cell precursors. They are involved in regulation of B-cell proliferation.
Antigens associated with specific proteins of the human adult T-cell immunodeficiency virus (HIV); also called HTLV-III-associated and lymphadenopathy-associated virus (LAV) antigens.
Measure of histocompatibility at the HL-A locus. Peripheral blood lymphocytes from two individuals are mixed together in tissue culture for several days. Lymphocytes from incompatible individuals will stimulate each other to proliferate significantly (measured by tritiated thymidine uptake) whereas those from compatible individuals will not. In the one-way MLC test, the lymphocytes from one of the individuals are inactivated (usually by treatment with MITOMYCIN or radiation) thereby allowing only the untreated remaining population of cells to proliferate in response to foreign histocompatibility antigens.
Elements of limited time intervals, contributing to particular results or situations.
An increased reactivity to specific antigens mediated not by antibodies but by cells.
A class of animal lectins that bind to carbohydrate in a calcium-dependent manner. They share a common carbohydrate-binding domain that is structurally distinct from other classes of lectins.
A group of differentiation surface antigens, among the first to be discovered on thymocytes and T-lymphocytes. Originally identified in the mouse, they are also found in other species including humans, and are expressed on brain neurons and other cells.
Reduction in the number of lymphocytes.
RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.
The type species of LENTIVIRUS and the etiologic agent of AIDS. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte.
Antigens stimulating the formation of, or combining with heterophile antibodies. They are cross-reacting antigens found in phylogenetically unrelated species.
A class of immunoglobulin bearing mu chains (IMMUNOGLOBULIN MU-CHAINS). IgM can fix COMPLEMENT. The name comes from its high molecular weight and originally being called a macroglobulin.
Glycoproteins expressed on cortical thymocytes and on some dendritic cells and B-cells. Their structure is similar to that of MHC Class I and their function has been postulated as similar also. CD1 antigens are highly specific markers for human LANGERHANS CELLS.
One of the mechanisms by which CELL DEATH occurs (compare with NECROSIS and AUTOPHAGOCYTOSIS). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA; (DNA FRAGMENTATION); at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth.
Class I-restricted activation of CD8-POSITIVE LYMPHOCYTES resulting from ANTIGEN PRESENTATION of exogenous ANTIGENS (cross-presentation). This is in contrast to normal activation of these lymphocytes (direct-priming) which results from presentation of endogenous antigens.
Naturally occurring or experimentally induced animal diseases with pathological processes sufficiently similar to those of human diseases. They are used as study models for human diseases.
Immunologic techniques based on the use of: (1) enzyme-antibody conjugates; (2) enzyme-antigen conjugates; (3) antienzyme antibody followed by its homologous enzyme; or (4) enzyme-antienzyme complexes. These are used histologically for visualizing or labeling tissue specimens.
Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors.
Any of several ways in which living cells of an organism communicate with one another, whether by direct contact between cells or by means of chemical signals carried by neurotransmitter substances, hormones, and cyclic AMP.
Specialized tissues that are components of the lymphatic system. They provide fixed locations within the body where a variety of LYMPHOCYTES can form, mature and multiply. The lymphoid tissues are connected by a network of LYMPHATIC VESSELS.
A major histocompatibily complex class I-like protein that plays a unique role in the presentation of lipid ANTIGENS to NATURAL KILLER T-CELLS.
A proinflammatory cytokine produced primarily by T-LYMPHOCYTES or their precursors. Several subtypes of interleukin-17 have been identified, each of which is a product of a unique gene.
Molecule composed of the non-covalent association of the T-cell antigen receptor (RECEPTORS, ANTIGEN, T-CELL) with the CD3 complex (ANTIGENS, CD3). This association is required for the surface expression and function of both components. The molecule consists of up to seven chains: either the alpha/beta or gamma/delta chains of the T-cell receptor, and four or five chains in the CD3 complex.
Antibodies that react with self-antigens (AUTOANTIGENS) of the organism that produced them.
A melanosome-associated protein that plays a role in the maturation of the MELANOSOME.
Combinations of diagnostic or therapeutic substances linked with specific immune substances such as IMMUNOGLOBULINS; MONOCLONAL ANTIBODIES; or ANTIGENS. Often the diagnostic or therapeutic substance is a radionuclide. These conjugates are useful tools for specific targeting of DRUGS and RADIOISOTOPES in the CHEMOTHERAPY and RADIOIMMUNOTHERAPY of certain cancers.
Nuclear antigens encoded by VIRAL GENES found in HUMAN HERPESVIRUS 4. At least six nuclear antigens have been identified.
A membrane glycoprotein and differentiation antigen expressed on the surface of T-cells that binds to CD40 ANTIGENS on B-LYMPHOCYTES and induces their proliferation. Mutation of the gene for CD40 ligand is a cause of HYPER-IGM IMMUNODEFICIENCY SYNDROME, TYPE 1.
Immunoglobulins produced in response to VIRAL ANTIGENS.
The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood MONOCYTES. Main types are PERITONEAL MACROPHAGES; ALVEOLAR MACROPHAGES; HISTIOCYTES; KUPFFER CELLS of the liver; and OSTEOCLASTS. They may further differentiate within chronic inflammatory lesions to EPITHELIOID CELLS or may fuse to form FOREIGN BODY GIANT CELLS or LANGHANS GIANT CELLS. (from The Dictionary of Cell Biology, Lackie and Dow, 3rd ed.)
The movement of cells from one location to another. Distinguish from CYTOKINESIS which is the process of dividing the CYTOPLASM of a cell.
Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely.
A group of the D-related HLA antigens found to differ from the DR antigens in genetic locus and therefore inheritance. These antigens are polymorphic glycoproteins comprising alpha and beta chains and are found on lymphoid and other cells, often associated with certain diseases.
A heterodimeric cytokine that plays a role in innate and adaptive immune responses. Interleukin-12 is a 70 kDa protein that is composed of covalently linked 40 kDa and 35 kDa subunits. It is produced by DENDRITIC CELLS; MACROPHAGES and a variety of other immune cells and plays a role in the stimulation of INTERFERON-GAMMA production by T-LYMPHOCYTES and NATURAL KILLER CELLS.
Mice homozygous for the mutant autosomal recessive gene "scid" which is located on the centromeric end of chromosome 16. These mice lack mature, functional lymphocytes and are thus highly susceptible to lethal opportunistic infections if not chronically treated with antibiotics. The lack of B- and T-cell immunity resembles severe combined immunodeficiency (SCID) syndrome in human infants. SCID mice are useful as animal models since they are receptive to implantation of a human immune system producing SCID-human (SCID-hu) hematochimeric mice.
Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis.
Recombinant proteins produced by the GENETIC TRANSLATION of fused genes formed by the combination of NUCLEIC ACID REGULATORY SEQUENCES of one or more genes with the protein coding sequences of one or more genes.
A positive regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (GENE EXPRESSION REGULATION), mRNAs (RNA, MESSENGER), and proteins.
Multi-subunit proteins which function in IMMUNITY. They are produced by B LYMPHOCYTES from the IMMUNOGLOBULIN GENES. They are comprised of two heavy (IMMUNOGLOBULIN HEAVY CHAINS) and two light chains (IMMUNOGLOBULIN LIGHT CHAINS) with additional ancillary polypeptide chains depending on their isoforms. The variety of isoforms include monomeric or polymeric forms, and transmembrane forms (B-CELL ANTIGEN RECEPTORS) or secreted forms (ANTIBODIES). They are divided by the amino acid sequence of their heavy chains into five classes (IMMUNOGLOBULIN A; IMMUNOGLOBULIN D; IMMUNOGLOBULIN E; IMMUNOGLOBULIN G; IMMUNOGLOBULIN M) and various subclasses.
A calcium-dependent pore-forming protein synthesized in cytolytic LYMPHOCYTES and sequestered in secretory granules. Upon immunological reaction between a cytolytic lymphocyte and a target cell, perforin is released at the plasma membrane and polymerizes into transmembrane tubules (forming pores) which lead to death of a target cell.
A negative regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (GENE EXPRESSION REGULATION), mRNAs (RNA, MESSENGER), and proteins.
A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed)
DNA sequences encoding the beta chain of the T-cell receptor. The genomic organization of the TcR beta genes is essentially the same in all species and is similar to the organization of Ig genes.
Histochemical localization of immunoreactive substances using labeled antibodies as reagents.
A variation of the PCR technique in which cDNA is made from RNA via reverse transcription. The resultant cDNA is then amplified using standard PCR protocols.
Ordered rearrangement of T-cell variable gene regions coding for the beta-chain of antigen receptors.
Allelic alloantigens often responsible for weak graft rejection in cases when (major) histocompatibility has been established by standard tests. In the mouse they are coded by more than 500 genes at up to 30 minor histocompatibility loci. The most well-known minor histocompatibility antigen in mammals is the H-Y antigen.
The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES.
An experimental animal model for central nervous system demyelinating disease. Inoculation with a white matter emulsion combined with FREUND'S ADJUVANT, myelin basic protein, or purified central myelin triggers a T cell-mediated immune response directed towards central myelin. The pathologic features are similar to MULTIPLE SCLEROSIS, including perivascular and periventricular foci of inflammation and demyelination. Subpial demyelination underlying meningeal infiltrations also occurs, which is also a feature of ENCEPHALOMYELITIS, ACUTE DISSEMINATED. Passive immunization with T-cells from an afflicted animal to a normal animal also induces this condition. (From Immunol Res 1998;17(1-2):217-27; Raine CS, Textbook of Neuropathology, 2nd ed, p604-5)
Includes the spectrum of human immunodeficiency virus infections that range from asymptomatic seropositivity, thru AIDS-related complex (ARC), to acquired immunodeficiency syndrome (AIDS).
Genetic loci in the vertebrate major histocompatibility complex that encode polymorphic products which control the immune response to specific antigens. The genes are found in the HLA-D region in humans and in the I region in mice.
The hepatitis B antigen within the core of the Dane particle, the infectious hepatitis virion.
The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.
The phenotypic manifestation of a gene or genes by the processes of GENETIC TRANSCRIPTION and GENETIC TRANSLATION.
Large, phagocytic mononuclear leukocytes produced in the vertebrate BONE MARROW and released into the BLOOD; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles.
A family of transcription factors characterized by the presence of highly conserved calcineurin- and DNA-binding domains. NFAT proteins are activated in the CYTOPLASM by the calcium-dependent phosphatase CALCINEURIN. They transduce calcium signals to the nucleus where they can interact with TRANSCRIPTION FACTOR AP-1 or NF-KAPPA B and initiate GENETIC TRANSCRIPTION of GENES involved in CELL DIFFERENTIATION and development. NFAT proteins stimulate T-CELL activation through the induction of IMMEDIATE-EARLY GENES such as INTERLEUKIN-2.
Cytokine that stimulates the proliferation of T-LYMPHOCYTES and shares biological activities with IL-2. IL-15 also can induce proliferation and differentiation of B-LYMPHOCYTES.
The capacity of a normal organism to remain unaffected by microorganisms and their toxins. It results from the presence of naturally occurring ANTI-INFECTIVE AGENTS, constitutional factors such as BODY TEMPERATURE and immediate acting immune cells such as NATURAL KILLER CELLS.
Glycoproteins expressed on all mature T-cells, thymocytes, and a subset of mature B-cells. Antibodies specific for CD5 can enhance T-cell receptor-mediated T-cell activation. The B-cell-specific molecule CD72 is a natural ligand for CD5. (From Abbas et al., Cellular and Molecular Immunology, 2d ed, p156)
In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships.
Cell surface molecules on cells of the immune system that specifically bind surface molecules or messenger molecules and trigger changes in the behavior of cells. Although these receptors were first identified in the immune system, many have important functions elsewhere.

The hematopoietic-specific adaptor protein gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors. (1/7520)

BACKGROUND: The adaptor protein Gads is a Grb2-related protein originally identified on the basis of its interaction with the tyrosine-phosphorylated form of the docking protein Shc. Gads protein expression is restricted to hematopoietic tissues and cell lines. Gads contains a Src homology 2 (SH2) domain, which has previously been shown to have a similar binding specificity to that of Grb2. Gads also possesses two SH3 domains, but these have a distinct binding specificity to those of Grb2, as Gads does not bind to known Grb2 SH3 domain targets. Here, we investigated whether Gads is involved in T-cell signaling. RESULTS: We found that Gads is highly expressed in T cells and that the SLP-76 adaptor protein is a major Gads-associated protein in vivo. The constitutive interaction between Gads and SLP-76 was mediated by the carboxy-terminal SH3 domain of Gads and a 20 amino-acid proline-rich region in SLP-76. Gads also coimmunoprecipitated the tyrosine-phosphorylated form of the linker for activated T cells (LAT) adaptor protein following cross-linking of the T-cell receptor; this interaction was mediated by the Gads SH2 domain. Overexpression of Gads and SLP-76 resulted in a synergistic augmentation of T-cell signaling, as measured by activation of nuclear factor of activated T cells (NFAT), and this cooperation required a functional Gads SH2 domain. CONCLUSIONS: These results demonstrate that Gads plays an important role in T-cell signaling via its association with SLP-76 and LAT. Gads may promote cross-talk between the LAT and SLP-76 signaling complexes, thereby coupling membrane-proximal events to downstream signaling pathways.  (+info)

Tyrosine phosphorylation and complex formation of Cbl-b upon T cell receptor stimulation. (2/7520)

Cbl-b, a mammalian homolog of Cbl, consists of an N-terminal region (Cbl-b-N) highly homologous to oncogenic v-Cbl, a Ring finger, and a C-terminal region containing multiple proline-rich stretches and potential tyrosine phosphorylation sites. In the present study, we demonstrate that upon engagement of the T cell receptor (TCR), endogenous Cbl-b becomes rapidly tyrosine-phosphorylated. In heterogeneous COS-1 cells, Cbl-b was phosphorylated on tyrosine residues by both Syk- (Syk/Zap-70) and Src- (Fyn/Lck) family kinases, with Syk kinase inducing the most prominent effect. Syk associates and phosphorylates Cbl-b in Jurkat T cells. A Tyr-316 Cbl-binding site in Syk was required for the association with and for the maximal tyrosine phosphorylation of Cbl-b. Mutation at a loss-of-function site (Gly-298) in Cbl-b-N disrupts its interaction with Syk. Cbl-b constitutively binds Grb2 and becomes associated with Crk-L upon TCR stimulation. The Grb2- and the Crk-L-binding regions were mapped to the C-terminus of Cbl-b. The Crk-L-binding sites were further determined to be Y655DVP and Y709KIP, with the latter being the primary binding site. Taken together, these results implicate that Cbl-b is involved in TCR-mediated intracellular signaling pathways.  (+info)

Crystal structures of two H-2Db/glycopeptide complexes suggest a molecular basis for CTL cross-reactivity. (3/7520)

Two synthetic O-GlcNAc-bearing peptides that elicit H-2Db-restricted glycopeptide-specific cytotoxic T cells (CTL) have been shown to display nonreciprocal patterns of cross-reactivity. Here, we present the crystal structures of the H-2Db glycopeptide complexes to 2.85 A resolution or better. In both cases, the glycan is solvent exposed and available for direct recognition by the T cell receptor (TCR). We have modeled the complex formed between the MHC-glycopeptide complexes and their respective TCRs, showing that a single saccharide residue can be accommodated in the standard TCR-MHC geometry. The models also reveal a possible molecular basis for the observed cross-reactivity patterns of the CTL clones, which appear to be influenced by the length of the CDR3 loop and the nature of the immunizing ligand.  (+info)

Thymic selection by a single MHC/peptide ligand: autoreactive T cells are low-affinity cells. (4/7520)

In H2-M- mice, the presence of a single peptide, CLIP, bound to MHC class II molecules generates a diverse repertoire of CD4+ cells. In these mice, typical self-peptides are not bound to class II molecules, with the result that a very high proportion of H2-M- CD4+ cells are responsive to the various peptides displayed on normal MHC-compatible APC. We show here, however, that such "self" reactivity is controlled by low-affinity CD4+ cells. These cells give spectacularly high proliferative responses but are virtually unreactive in certain other assays, e.g., skin graft rejection; responses to MHC alloantigens, by contrast, are intense in all assays. Possible explanations for why thymic selection directed to a single peptide curtails self specificity without affecting alloreactivity are discussed.  (+info)

Protection against lymphocytic choriomeningitis virus infection induced by a reduced peptide bond analogue of the H-2Db-restricted CD8(+) T cell epitope GP33. (5/7520)

Recent investigations have suggested that pseudopeptides containing modified peptide bonds might advantageously replace natural peptides in therapeutic strategies. We have generated eight reduced peptide bond Psi(CH2-NH) analogues corresponding to the H-2Db-restricted CD8(+) T cell epitope (called GP33) of the glycoprotein of the lymphocytic choriomeningitis virus. One of these pseudopeptides, containing a reduced peptide bond between residues 6 and 7 (Psi(6-7)), displayed very similar properties of binding to major histocompatibility complex (MHC) and recognition by T cell receptor transgenic T cells specific for GP33 when compared with the parent peptide. We assessed in vitro and in vivo the proteolytic resistance of GP33 and Psi(6-7) and analyzed its contribution to the priming properties of these peptides. The Psi(6-7) analogue exhibited a dramatically increased proteolytic resistance when compared with GP33, and we show for the first time that MHC-peptide complexes formed in vivo with a pseudopeptide display a sustained half-life compared with the complexes formed with the natural peptide. Furthermore, in contrast to immunizations with GP33, three injections of Psi(6-7) in saline induced significant antiviral protection in mice. The enhanced ability of Psi(6-7) to induce antiviral protection may result from the higher stability of the analogue and/or of the MHC-analogue complexes.  (+info)

Clinical significance of decreased zeta chain expression in peripheral blood lymphocytes of patients with head and neck cancer. (6/7520)

Patients with squamous cell carcinoma of the head and neck (SCCHN) frequently have impaired immune responses. Alterations in T-cell receptor-associated signaling molecules in tumor-infiltrating as well as circulating lymphocytes have been reported in these patients. Using quantitative flow cytometry analysis, we have demonstrated that expression of the zeta chain is significantly decreased relative to normal controls in both CD8+ and CD4+ T cells as well as CD3- CD56+ CD16+ natural killer cells in the peripheral blood of patients with SCCHN who, as a result of previous therapies, have no evident disease. Patients with a more aggressive type of SCCHN and those who experienced a recurrence or had a second primary cancer within the last 2 years of the study had the lowest zeta chain expression. In addition, SCCHN patients showed a significantly greater spontaneous ex vivo apoptosis, as measured by a terminal deoxynucleotide transferase-mediated dUTP nick end labeling assay, in PBMCs, compared to normal controls. The observed decreased expression of zeta in T and natural killer cells coincided but did not directly correlate with significantly increased spontaneous apoptosis of lymphocytes obtained from treated patients with no evident disease. The results suggest that in patients with SCCHN, zeta chain defects and lymphocyte apoptosis are manifestations of long-lasting negative effects of tumor on the immune system.  (+info)

Tyrosine 319, a newly identified phosphorylation site of ZAP-70, plays a critical role in T cell antigen receptor signaling. (7/7520)

Following T cell antigen receptor (TCR) engagement, the protein tyrosine kinase (PTK) ZAP-70 is rapidly phosphorylated on several tyrosine residues, presumably by two mechanisms: an autophosphorylation and a trans-phosphorylation by the Src-family PTK Lck. These events have been implicated in both positive and negative regulation of ZAP-70 activity and in coupling this PTK to downstream signaling pathways in T cells. We show here that Tyr315 and Tyr319 in the interdomain B of ZAP-70 are autophosphorylated in vitro and become phosphorylated in vivo upon TCR triggering. Moreover, by mutational analysis, we demonstrate that phosphorylation of Tyr319 is required for the positive regulation of ZAP-70 function. Indeed, overexpression in Jurkat cells and in a murine T cell hybridoma of a ZAP-70 mutant in which Tyr319 was replaced by phenylalanine (ZAP-70-Y319F) dramatically impaired anti-TCR-induced activation of the nuclear factor of activated T cells and interleukin-2 production, respectively. Surprisingly, an analogous mutation of Tyr315 had little or no effect. The inhibitory effect of ZAP-70-Y319F correlated with a substantial loss of its activation-induced tyrosine phosphorylation and up-regulation of catalytic activity, as well as with a decreased in vivo capacity to phosphorylate known ZAP-70 substrates, such as SLP-76 and LAT. Collectively, our data reveal the pivotal role of Tyr319 phosphorylation in the positive regulation of ZAP-70 and in TCR-mediated signaling.  (+info)

T-cell stimulation through the T-cell receptor/CD3 complex regulates CD2 lateral mobility by a calcium/calmodulin-dependent mechanism. (8/7520)

T lymphocyte activation through the T cell receptor (TCR)/CD3 complex alters the avidity of the cell surface adhesion receptor CD2 for its ligand CD58. Based on the observations that activation-associated increases in intracellular [Ca2+] ([Ca2+]i) strengthen interactions between T cells and antigen-presenting cells, and that the lateral mobility of cell surface adhesion receptors is an important regulator of cellular adhesion strength, we postulated that [Ca2+]i controls CD2 lateral mobility at the T cell surface. Human Jurkat T leukemia cells were stimulated by antibody-mediated cross-linking of the TCR/CD3 complex. CD2 was labeled with a fluorescently conjugated monoclonal antibody. Quantitative fluorescence microscopy techniques were used to measure [Ca2+]i and CD2 lateral mobility. Cross-linking of the TCR/CD3 complex caused an immediate increase in [Ca2+]i and, 10-20 min later, a decrease in the fractional mobility of CD2 from the control value of 68 +/- 1% to 45 +/- 2% (mean +/- SEM). One to two hours after cell stimulation the fractional mobility spontaneously returned to the control level. Under these and other treatment conditions, the fraction of cells with significantly elevated [Ca2+]i was highly correlated with the fraction of cells manifesting significantly reduced CD2 mobility. Pretreatment of cells with a calmodulin inhibitor or a calmodulin-dependent kinase inhibitor prevented Ca2+-mediated CD2 immobilization, and pretreatment of cells with a calcineurin phosphatase inhibitor prevented the spontaneous reversal of CD2 immobilization. These data suggest that T cell activation through the TCR/CD3 complex controls CD2 lateral mobility by a Ca2+/calmodulin-dependent mechanism, and that this mechanism may involve regulated phosphorylation and dephosphorylation of CD2 or a closely associated protein.  (+info)

Cho, HI, et al. (2018) A novel Epstein-Barr virus-latent membrane protein-1-specific T-cell receptor for TCR gene therapy. Br. J. Cancer. 2018 Jan 23;. PM ID: ...
The guanosine triphosphate (GTP)-binding proteins include signal-transducing heterotrimeric G proteins (for example, Gs, Gi), smaller GTP-binding proteins that function in protein sorting, and the oncogenic protein p21ras. The T cell receptor complexes CD4-p56lck and CD8-p56lck were found to include a 32- to 33-kilodalton phosphoprotein (p32) that was recognized by an antiserum to a consensus GTP-binding region in G proteins. Immunoprecipitated CD4 and CD8 complexes bound GTP and hydrolyzed it to guanosine diphosphate (GDP). The p32 protein was covalently linked to [alpha-32P]GTP by ultraviolet photoaffinity labeling. These results demonstrate an interaction between T cell receptor complexes and an intracellular GTP-binding protein. ...
2P5E: Crystal structures of high affinity human T-cell receptors bound to peptide major histocompatibility complex reveal native diagonal binding geometry
The fine specificity of T cell recognition of peptide analogues of the influenza nucleoprotein epitope, NP 383-391 SRYWAIRTR, was studied using HLA B27-restricted influenza-specific cytotoxic T cell (CTL) clones, of defined T cell receptor (TcR) usage, derived from unrelated individuals following natural infection. Even conservative amino acid substitutions of the peptide residues P4, P7 and P8 influenced CTL recognition. These side chains are probably directly contacted by the TcR. CTL clones which used the TcR V alpha 14 gene segment (but not those using TcR V alpha 12) were also sensitive to P1 substitutions, suggesting that the TcR alpha chain of these clones lies over the N terminus of bound peptide, and that the footprint of certain TcR can span all exposed residues of a peptide bound to a major histocompatibility complex class I molecule. These results, taken together with previous structural and functional data, suggest that, for nonamer peptides bound to HLA B27, P1, P4 and P8 are flag
1OSZ: Differential thymic selection outcomes stimulated by focal structural alteration in peptide/major histocompatibility complex ligands.
The C-type lectin CD161 is expressed by a large proportion of human T lymphocytes of all lineages, including a population known as mucosal-associated invariant T (MAIT) cells. To understand whether different T cell subsets expressing CD161 have similar properties, we examined these populations in parallel using mass cytometry and mRNA microarray approaches. The analysis identified a conserved CD161++/MAIT cell transcriptional signature enriched in CD161+CD8+ T cells, which can be extended to CD161+ CD4+ and CD161+TCR gamma delta+ T cells. Furthermore, this led to the identification of a shared innate-like, TCR-independent response to interleukin (IL)-12 plus IL-18 by different CD161-expressing T cell populations. This response was independent of regulation by CD161, which acted as a costimulatory molecule in the context of T cell receptor stimulation. Expression of CD161 hence identifies a transcriptional and functional phenotype, shared across human T lymphocytes and independent of both T cell ...
Interest in the role of CD5 in lymphocyte development has grown considerably in light of recent data suggesting that CD5 functions to negatively regulate signaling through the B and T cell antigen receptors ((16), (17)). In this study, we examined CD5 expression during normal thymocyte development and in mice with defects in thymocyte maturation. Our results demonstrate a critical role for pre-TCR and TCR signals, and notably TCR avidity, in regulating CD5 surface expression.. Early DN thymocytes express very low levels of CD5 independent of their ability to undergo TCR gene rearrangement, and therefore independent of their ability to express pre-TCR and/or TCR complexes. That the pre-TCR is not required for initial CD5 expression on early DN thymocytes is not surprising, as previous studies have documented very low levels of CD5 on pro-T cells in the thymus ((46)). Of significance, however, is that signals transduced by the pre-TCR upregulate CD5, and that the level of CD5 surface expression ...
In this study, we have shown that bivalent anti-CD3 delivers a partial TCR signal that renders Th1 clones hyporesponsive. This signal consists of phosphorylation of several components of the TCR complex, (bands representing CD3ε, CD3δ), ZAP-70 association, and partial phosphorylation of TCR ζ; in the absence of cross-linking, there is a relatively greater induction of the phosphorylated p21 ζ as compared with the p23 ζ band species evident in T cell clones. Presently, it is unclear what the p21 and p23 forms of ζ represent. p21 induction appears to be sufficient for association of the ZAP-70 kinase with the TCR complex, whereas p23 induction and ZAP-70 phosphorylation appear to be interrelated events. Indeed, the low level of ZAP-70 phosphorylation observed in the noncross-linked situation correlates with the small amount of p23 ζ that is generated. In a recent study, Weist et al. ((28)) proposed that the p23 form of ζ observed in thymocytes upon in vitro stimulation depends on greater ...
Engagement of the T-cell receptor (TCR) results in the activation of Lck/Fyn and ZAP-70/Syk tyrosine kinases. Lck-mediated tyrosine phosphorylation of
Our study demonstrates for the first time that treatment with RTL after onset of MCAO reduces cortical and total infarct size, inhibits infiltrating inflammatory cells, particularly activated macrophages/microglial cells and DCs, into postischemic brain, and partially preserves spleen cell numbers that are typically ablated after MCAO. This result was specific to RTL551 treatment in C57BL/6 male mice and verified using a humanized RTL1000 construct to treat MCAO in HLA-DR2-Tg mice. The results clearly show that the therapeutic activity of RTL requires a neuroantigen peptide (mouse or human MOG-35-55) tethered to an MHC moiety that closely matches the Class II of the treated mouse strain (I-Ab for C57BL/6 mice and HLA-DR2 for DR2-Tg mice). In contrast, treatment of C57BL/6 mice with RTL553 comprised of I-Ab coupled to I-Ea-52-68 (a nonneuroantigen peptide) and RTL342M comprised of HLA-DR2 (nonmatched MHC Class II) coupled to mMOG-35-55 peptide did not have therapeutic effects.. Beyond the ...
The human T cell receptor for antigen (Ti) has recently been identified on IL-2 dependent T cell clones as a 90 kd disulfide-linked heterodimer comprised of one 49-51 kd alpha (alpha) and one 43 kd beta (beta) chain. These subunits are noncovalently associated with a monomorphic 20-25 kd T3 molecule. Here, we produce monoclonal antibodies to a human tumor (REX) derived from an earlier stage of thymic differentiation in order to determine whether clonotypic structures are expressed and to define the ontogeny of Ti. The results of SDS-PAGE and peptide map analyses indicate that an homologous T3-associated heterodimer is synthesized and expressed by REX. This glycoprotein shares several peptides in common with clonotypic structures on an IL-2 dependent T cell clone. In addition, similar Ti related molecules appear during intrathymic ontogeny in parallel with surface T3 expression. The latter findings provide the structural basis for the immunological competence observed exclusively within the T3+ thymocyte
The prevailing view of thymocyte selection is that the fate of developing cells is dictated exclusively by the affinity/avidity of the expressed TCR for self-MHC/self-ligand. We hypothesize that there is significant plasticity in the signaling processes that control T cell development and that the ability to fine-tune the TCR signaling response, through the regulated expression of molecules that positively or negatively impact the TCR signaling response operates to maximize the TCR repertoire. One example of a fine-tuning molecule that was previously characterized is the cell surface protein CD5. We found that CD5 is an inhibitory tuning receptor, and its surface expression is directly and proportionately regulated by the affinity of the TCR for selecting ligand. In order to identify additional candidates for TCR-tuning, we employed a TCR transgenic experimental system where TCR expression was fixed on all developing thymocytes and where the affinity of the positively selecting ...
The human T cell receptor for antigen (Ti) has recently been identified on IL-2 dependent T cell clones as a 90 kd disulfide-linked heterodimer comprised of one 49-51 kd alpha (alpha) and one 43 kd beta (beta) chain. These subunits are noncovalently associated with a monomorphic 20-25 kd T3 molecule. Here, we produce monoclonal antibodies to a human tumor (REX) derived from an earlier stage of thymic differentiation in order to determine whether clonotypic structures are expressed and to define the ontogeny of Ti. The results of SDS-PAGE and peptide map analyses indicate that an homologous T3-associated heterodimer is synthesized and expressed by REX. This glycoprotein shares several peptides in common with clonotypic structures on an IL-2 dependent T cell clone. In addition, similar Ti related molecules appear during intrathymic ontogeny in parallel with surface T3 expression. The latter findings provide the structural basis for the immunological competence observed exclusively within the T3+ thymocyte
Patients who were previously treated with Adaptimmune NY-ESO-1ᶜ²⁵⁹T cells are asked to take part in this study to see how safe NY-ESO-1ᶜ²⁵⁹T cells are and what
T lymphocytes are essential for the functioning of the adaptive immune system. This is demonstrated by genetic or virus induced human immunodeficiencies resulting from a lack of T-cells. T-cells recognize changes in their environment through a specific T-cell receptor (TCR) protein expressed on their surface. This receptor binds to peptide antigens presented in the context of major histocompatibility complex (MHC) proteins on the surface of antigen presenting cells. TCR binding to its ligand causes signaling that re-programs the cell by turning on new genes. TCR first gets expressed on the surface of T cell precursors that also have two co-receptors on their surface named CD4 and CD8. These double positive (DP) thymocytes have the business of generating all the T lymphocytes in the body. Re-programming by new gene expression is important for the development of the thymocyte precursors of T cells in the thymus and for the response of T lymphocytes in peripheral lymphoid organs. We are interested ...
Anti-isotypic reagents against the human T cell receptor (TcR) were made by immunizing rabbits with peptides which corresponded to sites within the co
Read independent reviews on MILLIPLEX® MAP 7-plex Human T Cell Receptor Signaling Kit - Phosphoprotein from MilliporeSigma on SelectScience
In the absence of foreign antigen, peripheral naive T cells continuously recirculate between different lymphoid organs, in which they interact frequently and shortly with self. We and others have shown that such interactions are required for the long-term survival of naïve T cells. In addition, these TCR/MHC interactions and the resulting associated signaling increase quantitatively T-cell responsiveness towards foreign antigens and influence their function and/or differentiation into effector or memory cells in response to stimulation. Our project is based on our recent data showing that peripheral ab and gd T cells can be subdivided into various subsets according to Ly-6C expression. Interestingly, in CD4 ab T cells, Ly-6C expression inversely correlates with the ability of these cells to interact with self, defining Ly-6C as a new sensor of T cell self-reactivity. In parallel, we are exploring the regulation of T-cell self-reactivity in the context of cancer. Indeed, T cells specific for ...
J Immunol 172:4709-4716, 2004. PMID: 15067046. Cascalho M, Platt JL. B cell-dependent T cell development. Acta Paediatr 93(Supplement 445):52-53, 2004. PMID: 15176721. Cascalho M, Platt JL. B cells and B cell products-helping to restore cellular immunity? Transfus Med Hemother 33:45-49, 2006. PMID: 16755301. Balin SJ, Cascalho M. The rate of mutation of a single gene. Nucleic Acids Res. 2010. 38:1575-82. PMID: 20007603 3. Fitness of cellular immunity and T cell receptor diversity. T cell diversity is generally thought to confer immune fitness. However which properties of immunity depend absolutely on TCR receptor diversity and the extent of diversity necessary for optimal function are not fully understood. My research conducted in collaboration with Dr. Platt revealed for the first time that significant contractions of the T cell receptor repertoire do not impair certain functions of cell-mediated immunity, such as defense against intracellular fungi and rejection of grafts disparate for minor ...
T lymphocytes are essential for the functioning of the adaptive immune system. This is demonstrated by genetic or virus induced human immunodeficiencies resulting from a lack of T-cells. T-cells recognize changes in their environment through a specific T-cell receptor (TCR) protein expressed on their surface. This receptor binds to peptide antigens presented in the context of major histocompatibility complex (MHC) proteins on the surface of antigen presenting cells. TCR binding to its ligand causes signaling that re-programs the cell by turning on new genes. TCR first gets expressed on the surface of T cell precursors that also have two co-receptors on their surface named CD4 and CD8. These double positive (DP) thymocytes have the business of generating all the T lymphocytes in the body. Re-programming by new gene expression is important for the development of the thymocyte precursors of T cells in the thymus and for the response of T lymphocytes in peripheral lymphoid organs. We are interested ...
A type of T cell apoptosis that occurs towards the end of the expansion phase following the initial activation of mature T cells by antigen and is triggered by T cell receptor stimulation and signals transmitted via various surface-expressed members of th…
The T-cell repertoire found in the periphery is thought to be shaped by two developmental events in the thymus that involve the antigen receptors of T lymphocytes. First, interactions between T cells and major histocompatibility complex (MHC) molecules select a T-cell repertoire skewed towards recog …
Results High expression of αEβ7 was noted on CD8+ and CD4+ Th9 cells, while α4β7 was expressed on CD8+, Th2 and Th17 cells. T cell receptor stimulation and transforming growth factor β were key inducers of αEβ7 on human T cells, while butyric acid suppressed αEβ7. In comparison to α4β7 blockade via vedolizumab, blockade of β7 via etrolizumab surrogate antibody superiorly reduced colonic numbers of CD8+ and Th9 cells in vivo after 3 hours, while no difference was noted after 0.5 hours. AEβ7 expression was higher on CD8+ T cells from patients with IBD under vedolizumab therapy. ...
There is considerable controversy about the mechanism of T cell receptor (TCR) triggering, the process by which the TCR tranduces signals across the plasma membrane after binding to its ligand (an agonist peptide complexed with an MHC molecule). Three main types of mechanism have been proposed, which involve aggregation, conformational change and segregation. Here, we review recently published evidence for each type of mechanism and conclude that all three may be involved. This complexity may reflect the uniquely demanding nature of TCR-mediated antigen recognition, which requires the detection of a very weak signal (very rare foreign peptide-MHC ligands) in the presence of considerable noise (abundant self peptide-MHC molecules).
We have established a system of TCRαβ ablation by combining the IFN-inducible Mx-Cre transgene with a loxP-flanked TCR Cα gene together with a TCRα null allele. pI/pC injection leads to the deletion of Cα in 40% of peripheral mature CD4+ and 80% of CD8+ cells. After about 10 days, the level of expression of the TCR complex on the surface of the Cα-deficient cells has declined by 2.5-3 orders of magnitude, as assessed by staining for TCRβ and CD3. Assuming that staining intensity is roughly proportional to the number of surface-bound TCR complexes, and that about 30,000 such complexes are expressed on mature T cells (26, 27), we conclude that no more than 100 TCR complexes could be expressed on the surface of the Cα-deficient cells 10 days after induction of Cα deletion. To our surprise, we found that, on the basis of liposome-assisted flow cytometric analysis, low levels of TCRβ chains, likely in the order of 100 molecules per cell when we take analogous data from the literature into ...
Construction of the T-cell receptor The antibody is not the only protein that recognizes the antigen. The antigen-specific receptor of T lymphocytes does the same. It is simply called the T-cell receptor and is abbreviated as the T-cell receptor TCR. We can define the antigen as a compound capable of eliciting the formation of a …. CELL IMMUNITY. T-CELL receptors (TCRs) and their epitopes Read More ». ...
T-cell cross-reactivity is essential for effective immune surveillance, but has also been implicated as a pathway to autoimmunity. Previous studies have demonstrated that T-cell receptors (TCRs) that focus on a minimal motif within the peptide are able to facilitate a high level of T-cell cross-reactivity. However, the structural database shows that most TCRs exhibit less focussed antigen binding involving contact with more peptide residues. To further explore the structural features that allow the clonally expressed TCR to functionally engage with multiple peptide-major histocompatibility complexes (pMHCs), we examined the ILA1 CD8+ T-cell clone that responds to a peptide sequence derived from human telomerase reverse transcriptase (hTERT). The ILA1 TCR contacted its pMHC with a broad peptide-binding footprint encompassing spatially distant peptide residues. Despite the lack of focused TCR-peptide binding , the ILA1 T-cell clone was still cross-reactive. Overall, the TCR-peptide contacts ...
Mono-7D6-Fab co-potentiated TCR/CD3 signaling in response to weak pMHC antigens that possessed a critical minimal antigenic strength. Here, we present the main model of receptor co-potentiation by an otherwise intrinsically inert monovalent Fab (fig. S8). Ligation of TCR/CD3 by weak antigens induces weak signal transduction and weak T cell responses (fig. S8A). In contrast, ligation by anti-TCR/CD3 monovalent Fab is inert, inducing no classical signal transduction and producing no functional T cell response even though such Fab binding may induce biophysical alteration to the receptor (fig. S8B). The co-potentiation principle states that weak antigenic ligation plus intrinsically inert monovalent Fab ligation can synergize to enhance TCR signaling and T cell responses (fig. S8C).. The identification of specific properties displayed by Mono-7D6-Fab permitted an investigation of the co-potentiation concept. Mono-7D6-Fab did not impede pMHC:TCR interactions and did not intrinsically induce TCR/CD3 ...
TY - JOUR. T1 - The affinity of elongated membrane-tethered ligands determines potency of T cell receptor triggering. AU - Chen, Bing Mae. AU - Al-Aghbar, Mohammad Ameen. AU - Lee, Chien Hsin. AU - Chang, Tien Ching. AU - Su, Yu-Cheng. AU - Li, Ya Chen. AU - Chang, Shih En. AU - Chen, Chin Chuan. AU - Chung, Tsai Hua. AU - Liao, Yuan Chun. AU - Lee, Chau Hwang. AU - Roffler, Steve R.. PY - 2017/7/10. Y1 - 2017/7/10. N2 - T lymphocytes are important mediators of adoptive immunity but the mechanism of T cell receptor (TCR) triggering remains uncertain. The interspatial distance between engaged T cells and antigen-presenting cells (APCs) is believed to be important for topological rearrangement of membrane tyrosine phosphatases and initiation of TCR signaling. We investigated the relationship between ligand topology and affinity by generating a series of artificial APCs that express membrane-tethered anti-CD3 scFv with different affinities (OKT3, BC3, and 2C11) in addition to recombinant class I ...
CHO-Anti-Human T-cell receptor F(ab) stable cell line is clonally-derived from a CHO cell line, which has been transfected with an anti-human T-cell receptor F(ab) gene to allow expression of the F(ab). It is an example of a cell line transfected using our proprietary CBTGS gene screening and amplification system.
1. The regulation of the immune response: vaccine design, phage-based vaccines, Virus-like-particle vaccines, protein vaccines, Alzheimers Disease immunotherapy, induction of immune responses to self-antigens, correlates of vaccine efficacy, signaling in T cell development and activation, T cell receptor repertoire in Coeliac disease, T cell receptor repertoire of antigen-specific T cell lines ...
TY - JOUR. T1 - TCR clonotypes. T2 - molecular determinants of T-cell efficacy against HIV. AU - Lissina, Anya. AU - Chakrabarti, Lisa A. AU - Takiguchi, Masafumi. AU - Appay, Victor. PY - 2016/2. Y1 - 2016/2. N2 - Because of the enormous complexity and breadth of the overall HIV-specific CD8+ T-cell response, invaluable information regarding important aspects of T-cell efficacy against HIV can be sourced from studies performed on individual clonotypes. Data gathered from ex vivo and in vitro analyses of T-cell responses and viral evolution bring us one step closer towards deciphering the correlates of protection against HIV. HIV-responsive CD8+ T-cell populations are characterized by specific clonotypic immunodominance patterns and public TCRs. The TCR endows T-cells with two key features, important for the effective control of HIV: avidity and crossreactivity. While TCR avidity is a major determinant of CD8+ T-cell functional efficacy against the virus, crossreactivity towards wildtype and ...
T cells use their T-cell receptors (TCRs) to discriminate between lower-affinity self and higher affinity non-self pMHC antigens. Although the discriminatory power of the TCR is widely believed to be near-perfect, technical difficulties have hampered efforts to precisely quantify it. Here, we describe a method for measuring very low TCR/pMHC affinities, and use it to measure the discriminatory power of the TCR, and the factors affecting it. We find that TCR discrimination, although enhanced compared with conventional cell-surface receptors, is imperfect: primary human T cells can respond to pMHC with affinities as low as K D ~1 mM. The kinetic proofreading mechanism fit our data, providing the first estimates of both the time delay (2.8 s) and number of biochemical steps (2.67) that are consistent with the extraordinary sensitivity of antigen recognition. Our findings explain why self pMHC frequently induce autoimmune diseases and anti-tumour responses, and suggest ways to modify TCR discrimination.
Tumour necrosis factor family. Family of cytokines that form homotrimeric or heterotrimeric complexes. TNF mediates mature T-cell receptor-induced apoptosis through the p75 TNF receptor. ...
We will carry out deep sequencing of rearranged immunoglobulin (Ig) and T cell receptor (TCR) genes from lymphocytes in human subjects responding to several dis...
T Cell Receptor (TCR) V beta 4, 0.125 mg. The receptors on T cells consist of immunoglobulin like integral membrane glycoproteins containing 2 polypeptide subunits, alpha and beta, of similar molecular weight, 40 to 55 kD in the human.
To pursue our first goal, we have focused on developing advanced imaging techniques to understand the molecular interactions that underlie the process by which a particular T cell recognizes fragments of an antigen (peptide) that are bound to molecules of the major histocompatibility complex (MHC) and displayed on the surfaces of cells. These peptide-MHC complexes are then recognized by the T cell antigen receptor (TCR), an antibody-like molecule present on most T cells. The TCR is closely associated with the CD3 polypeptides, which mediate intracellular signaling through a kinase cascade. Our previous work and that of others characterized the biochemistry and genetics of TCRs, but in recent years we have focused on how these molecules operate in the larger context of T cell recognition, a context that includes other molecules on the T cell surface that work with the TCR, and on how ligand binding triggers T cell activation. Video microscopy and other advanced imaging techniques, such as ...
We will carry out deep sequencing of rearranged immunoglobulin (Ig) and T cell receptor (TCR) genes from lymphocytes in human subjects responding to several dis...
CRE-mediated transcriptional activation is involved in cAMP protection of T-cell receptor-induced apoptosis but not in cAMP potentiation of glucocorticoid-mediated programmed cell death ...
Clone REA651 recognizes the mouse V beta 10 T cell receptor (TCR Vβ10). The T cell receptor is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules. It is a disulfide-linked membrane-anchored heterodimeric glycoprotein normally consisting of the highly variable alpha and beta chains expressed as part of a complex with the invariant CD3 chain molecules. The α and β TCR chains are composed of constant and variable regions, each encoded by distinct gene segments. TCR Vβ10 is a variant of the TCR β chain and is expressed on T cells having the a haplotype, but not with the b and c haplotype of the TCRβ gene complex. Additional information: Clone REA651 displays negligible binding to Fc receptors. - Lëtzebuerg
T Cell Receptor (TCR) V beta-2, 0.1 mg. The receptors on T cells consist of immunoglobulin like integral membrane glycoproteins containing 2 polypeptide subunits, alpha and beta, of similar molecular weight, 40 to 55 kD in the human.
What happens when T cells detect suspicious activity in the body? Researchers from the TU Wien and the Medical University of Vienna have revealed that immune receptors of T cells operate in unsuspected ways.
It is not yet clear which are the activation signals underpinning this large expansion of polyclonal γδ T cells in this process. Proliferation was dependent on CD137L, IL2, and IL21, but the involvement of TCR signaling has not been tested. Although it is hard to conceive that aAPCs express the full array of TCR ligands for all expanded γδ T cells, engagement of TCR is suggested by the low TCR expression on generated Vδ2pos T cells and by the importance of CD137L for the expansion despite the absence of CD137 expression by γδ T cells prior expansion. Fisher and colleagues who coated B1 anti-γδTCR antibody on aAPCs showed it did not have a major role in γδ T-cell expansion even if this led to a better representation of Vδ2neg subsets. Gamma delta T cells have been shown to express HLA-I inhibitory receptors (7), so the absence of HLA-I expression by K562 as well as expression of activatory molecules such as NKG2D ligands may also play critical role in γδ T-cell activation.. Most ...
A trapped bead (right) decorated with a foreign antigen is actively placed on a T cell (left) and force is applied to facilitate recognition by the T cell receptor complex.
The Koelle lab will comprehensively define the CD4 and CD8 T cell epitopes in HSV-1 and HSV-2, using blood, skin lesion biopsy, eye, and brain samples, and using both culture-dependent and culture-independent methods based on T cell receptor sequencing and reconstruction.. ...
The Koelle lab will comprehensively define the CD4 and CD8 T cell epitopes in HSV-1 and HSV-2, using blood, skin lesion biopsy, eye, and brain samples, and using both culture-dependent and culture-independent methods based on T cell receptor sequencing and reconstruction.. ...
Researchers at National Jewish Health have answered a long-standing question about how the immune system selects T cells that recognize and attack potentially harmful invaders, while leaving alone a bodys own tissues.
Immune systems of vertebrates function via two types of effector cells, B and T cells, which are capable of antigen-specific recognition. The immunoglobulins, which serve as antigen receptors on B cells, have been well characterized with respect to gene structure, unlike the T-cell receptors. Recently, cDNA clones thought to correspond to the beta-chain locus of the human and mouse T-cell receptor have been described. The presumptive beta-chain clones detect gene rearrangement specifically in T-cell DNA and show homology with immunoglobulin light chains. The similarity of the T-cell beta-chain gene system to the immunoglobulin genes has been further demonstrated by the recent observation of variable- and constant-region gene segments as well as joining segments and putative diversity segments. We report here the characterization of cDNA and genomic clones encoding human T-cell receptor beta-chain genes. There are two constant-region genes (C beta 1 and C beta 2), each capable of rearrangement and
Immunological synapses are organized cell-cell junctions between T lymphocytes and APCs composed of an adhesion ring, the peripheral supramolecular activation cluster (pSMAC), and a central T cell receptor cluster, the central supramolecular activation cluster (cSMAC). In CD8+ cytotoxic T lymphocytes, the immunological synapse is thought to facilitate specific killing by confining cytotoxic agents to the synaptic cleft. We have investigated the interaction of human CTLs and helper T cells with supported planar bilayers containing ICAM-1. This artificial substrate provides identical ligands to CD4+ and CD8+ T cells, allowing a quantitative comparison. We found that cytotoxic T lymphocytes form a ring junction similar to a pSMAC in response to high surface densities of ICAM-1 in the planar bilayer. MICA, a ligand for NKG2D, facilitated the ring junction formation at lower surface densities of ICAM-1. ICAM-1 and MICA are upregulated in tissues by inflammation- and stress-associated signaling, ...
Thymic selection of natural killer-1+ natural T cells that express alpha beta T cell receptors requires a conserved beta 2-microglobulin-associated molecule, presumably CD1d, displayed by CD4+8+ thymocytes. Here we demonstrate that positive selection of natural T cells occurs independent of transporters associated with antigen presentation-1 (TAP-1) function. Moreover, natural T cells in TAP-1o/o mice are numerically expanded. Several H-2 class Ib molecules function in a TAP-independent manner, suggesting that if expressed in TAP-1o/o thymocytes, they could play a role in natural T cell development. Of these class Ib molecules, H-2TL is expressed by TAP-1o/o thymocytes. Moreover, we find that thymi of TL+ mice congenic or transgenic for H-2T18 also have a numerically expanded natural T cell repertoire compared with TL- mice. This expansion, as in TAP-1o/o thymi, is evident in each of the limited T cell receptor V beta chains expressed by natural T cells, suggesting that TL and CD1d impact ...
Engagement of the T-cell receptor (TCR) results in the activation of Lck/Fyn and ZAP-70/Syk tyrosine kinases. Lck-mediated tyrosine phosphorylation of signaling motifs (ITAMs) in the CD3-zeta subunits of the TCR is an initial step in the transduction of signaling cascades. However, zeta phosphorylation is also promoted by ZAP-70, as TCR-induced zeta phosphorylation is defective in ZAP-70-deficient T cells. We show that this defect is corrected by stable expression of ZAP-70, but not Syk, in primary and transformed T cells. Indeed, these proteins are differentially coupled to the TCR with a 5- to 10-fold higher association of ZAP-70 with zeta as compared to Syk. Low-level Syk-zeta binding is associated with significantly less Lck coupled to the TCR. Moreover, diminished coupling of Lck to zeta correlates with a poor phosphorylation of the positive regulatory tyr352 residue of Syk. Thus, recruitment of Lck into the TCR complex with subsequent zeta chain phosphorylation is promoted by ZAP-70 but ...
The requirements for tonic T-cell receptor (TCR) signaling in CD8+ memory T-cell generation and homeostasis are poorly defined. of SLP-76 and then acutely deprived of TCR-mediated signals persist in vivo in Naxagolide normal numbers for more than 40 weeks. Tonic TCR signals are not required for the transition of the memory pool toward a central memory phenotype but the absence of SLP-76 during memory homeostasis substantially alters the kinetics. Our data are consistent with a model in which tonic TCR signals are required at multiple stages of differentiation but are dispensable for memory CD8 T-cell persistence. Introduction Protection against recurrent infections resulting from the same pathogen is a hallmark of adaptive immunity. After acute infection by an intracellular pathogen naive CD8+ T cells expressing epitope-specific T-cell receptors (TCRs) are activated. The effector phase of the response is short with a rapid expansion of antigen-specific T cells and pathogen clearance. Rabbit ...
Signaling through the T cell antigen receptor (TCR) results both in rapid increases in tyrosine phosphorylation on a number of proteins and in the activation of the phosphatidylinositol pathway. It is not clear how stimulation of the TCR leads to these signaling events. Mutants of the Jurkat T cell …
Guanine nucleotide exchange factor (GEF) for RAB35 that acts as a regulator of T-cell receptor (TCR) internalization in TH2 cells (PubMed:20154091, PubMed:20937701, PubMed:24520163, PubMed:26774822). Acts by promoting the exchange of GDP to GTP, converting inactive GDP-bound RAB35 into its active GTP-bound form (PubMed:20154091, PubMed:20937701). Plays a role in clathrin-mediated endocytosis (PubMed:20154091). Controls cytokine production in TH2 lymphocytes by controlling the rate of TCR internalization and routing to endosomes: acts by mediating clathrin-mediated endocytosis of TCR via its interaction with the adapter protein complex 2 (AP-2) and GEF activity (PubMed:26774822). Dysregulation leads to impaired TCR down-modulation and recycling, affecting cytokine production in TH2 cells (PubMed:26774822 ...
T cells play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Clonal expansion of T cells correlating with disease activity has been observed in peripheral blood (PB) of SLE subjects. Recently, next-generation sequencing (NGS) of the T cell receptor (TCR) β loci has emerged as a sensitive way to measure the T cell repertoire. In this study, we utilized NGS to assess whether changes in T cell repertoire diversity in PB of SLE patients correlate with or predict changes in disease activity. Total RNA was isolated from the PB of 11 SLE patients. Each subject had three samples, collected at periods of clinical quiescence and at a flare. Twelve age-matched healthy controls (HC) were used for reference. NGS was used to profile the complementarity-determining region 3 (CDR3) of the rearranged TCR β loci. Relative to the HC, SLE patients (at quiescence) demonstrated a 2.2-fold reduction in repertoire diversity in a given PB volume (P |0.0002), a more uneven distribution of the
T cell development from immature CD4(+)CD8(+) double-positive (DP) thymocytes to the mature CD4 or CD8 single-positive (SP) stage requires proper T cell receptor (TCR) signaling. The current working model of thymocyte development is that the strength of the TCR-mediated signal - from little-or-none, through intermediate, to strong - received by the immature cells determines whether they will undergo death by neglect, positive selection, or negative selection, respectively. In recent years, several developmentally regulated, stage-specifically expressed proteins and miRNAs have been found that act like fine-tuners for signal transduction and propagation downstream of the TCR. This allows them to govern thymocyte positive selection. Here, we summarize recent findings on these molecules and suggest new concepts of TCR positive-selection signaling.
The T-cell antigen receptor (TCR) complex is composed of a ligand-binding subunit, the α and β chains, and a signaling subunit, namely the CD3ε, γ and δ chains and the TCRζ chain. This complex participates in T-cell activation upon the presentation of the antigen peptide (derived from the foreign antigen) bound to the MHC (Class I and Class II) residing on antigen-presenting cells (APCs), including dendritic cells, macrophages and B cells. Co-stimulatory receptors, such as CD2, CD28, CD4, CD8, and integrin molecules, contribute to signal transduction by modulating the response threshold. All the above components along with accessory proteins essential for MHC are a part of the immunological synapse that initiates T-cell activation. Protein tyrosine phosphorylation mediated by the Src family kinases Lck and Fyn, in turn regulated by CD45, is the initial event in TCR signaling. Lck is activated by the interaction of MHC and CD4 or CD8. It then induces the phosphorylation and activation of ...
T cell receptor antigen complex. Molecular model of the alphabeta T cell receptor bound to the influenza haemagglutinin antigen and MHC class II molecule HLA-DR1. T cell receptors are protein complexes found on the surface of a type of white blood cell called T lymphocytes (or T cells), part of the bodys immune system. Antigens (foreign proteins) are presented to T cell receptors by MHC molecules to effect an immune response. - Stock Image C025/1593
This study investigated whether fingolimod reduced newly produced T and B lymphocytes and T-cell receptor repertoire diversity in peripheral blood in patients
Using H-2Kd-restricted CTL clones, which are specific for a photoreactive derivative of the Plasmodium berghei circumsporozoite peptide PbCS(252-260) (SYIPSAEKI) and permit assessment of TCR-ligand interactions by TCR photoaffinity labeling, we have previously identified several peptide derivative variants for which TCR-ligand binding and the efficiency of Ag recognition deviated by fivefold or more. Here we report that the functional CTL response (cytotoxicity and IFN-gamma production) correlated with the rate of TCR-ligand complex dissociation, but not the avidity of TCR-ligand binding. While peptide antagonists exhibited very rapid TCR-ligand complex dissociation, slightly slower dissociation was observed for strong agonists. Conversely and surprisingly, weak agonists typically displayed slower dissociation than the wild-type agonists. Acceleration of TCR-ligand complex dissociation by blocking CD8 participation in TCR-ligand binding increased the efficiency of Ag recognition in cases where
To explore the possibility of an alternative strategy to treat hematological malignancies of HLA-A2+ HA-2-expressing patients transplanted with HLA-A2− donors, we isolated CMV-specific T cells from an HLA-A2− individual and transferred these T cells with HA-2-TCRs. For this purpose CMV-specific HLA-B7-restricted T cells (CMVB7-specific T cells) were FACS® sorted using CMVB7 tetramers stimulated with CMVB7 peptide-loaded, irradiated autologous PBMCs and transduced with the HA-2-TCR derived from the HA-2-specific T cell clone HA2.5, or with control retroviral vectors. By FACS® analyses we demonstrated that a high percentage of CMVB7-specific T cells was transduced (49-58%) and that the majority of HA-2-TCR α and β chain transduced T cells stained with the HA-2A2 tetramer (Fig. 6). Similar to the HA-2-TCR-transduced CMVA2-specific T cells, the CMVB7 tetramer staining was decreased on the HA-2-TCR-transduced CMVB7-specific T cells compared with the control-transduced CMVB7-specific T cells. ...
We tested for antigen recognition and T cell receptor (TCR)-ligand binding 12 peptide derivative variants on seven H-2Kd-restricted cytotoxic T lymphocytes (CTL) clones specific for a bifunctional photoreactive derivative of the Plasmodium berghei circumsporozoite peptide 252-260 (SYIPSAEKI). The derivative contained iodo-4-azidosalicylic acid in place of PbCS S-252 and 4-azidobenzoic acid on PbCS K-259. Selective photoactivation of the N-terminal photoreactive group allowed crosslinking to Kd molecules and photoactivation of the orthogonal group to TCR. TCR photoaffinity labeling with covalent Kd-peptide derivative complexes allowed direct assessment of TCR-ligand binding on living CTL. In most cases (over 80%) cytotoxicity (chromium release) and TCR-ligand binding differed by less than fivefold. The exceptions included (a) partial TCR agonists (8 cases), for which antigen recognition was five-tenfold less efficient than TCR-ligand binding, (b) TCR antagonists (2 cases), which were not recognized and
Adoptive T cell immunotherapy has shown promise in treating some cancers, but the challenge of isolating T cells with high avidity for tumor antigens limits large-scale applicability. T cell receptor (TCR) gene transfer employing high affinity TCRs recognizing defined tumor-associated antigens can potentially circumvent these challenges. Using a well-characterized murine model of adoptive T cell immunotherapy for established malignancy, we have demonstrated the feasibility of eliminating disseminated leukemia using T cells genetically modified by TCR gene transfer.We next examined the potential of targeting a clinically relevant tumor antigen, the transcription factor WT1, for which the expression patterns in normal and malignant cells are similar in mouse and man. WT1 is overexpressed in most leukemias and many solid tumors and its expression contributes to the malignant phenotype. The RMFPNAPYL peptide from WT1 is presented by HLA-A2 in humans, as well as by H-2Db in C57BL/6 mice, and has been ...
T-Cell Antigen Receptors: Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens (ANTIGENS, CD3). Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta (RECEPTORS, ANTIGEN, T-CELL, ALPHA-BETA) or gamma-delta (RECEPTORS, ANTIGEN, T-CELL, GAMMA-DELTA) chains.
Recognition by CD8,sup,+,/sup, cytotoxic T lymphocytes (CTLs) of antigenic peptides bound to major histocompatibility class (MHC) I molecules on target cells leads to sustained calcium mobilization and CTL degranulation resulting in perforin-dependent killing. We report that beta,sub,1,/sub, and beta,sub,3,/sub, integrin-mediated adhesion to extracellular matrix proteins on target cells and/or surfaces dramatically promotes CTL degranulation. CTLs, when adhered to fibronectin but not CTL in suspension, efficiently degranulate upon exposure to soluble MHC.peptide complexes, even monomeric ones. This adhesion induces recruitment and activation of the focal adhesion kinase Pyk2, the cytoskeleton linker paxillin, and the Src kinases Lck and Fyn in the contact site. The T cell receptor, by association with Pyk2, becomes part of this adhesion-induced activation cluster, which greatly increases its signaling ...
Alterations in peptide ligand that result in better or worse binding to MHC are effectively a change in concentration of pMHC ligand. This becomes especially significant in in vivo settings, where encounter with Ag is usually more rare. When comparing different peptide ligands, careful determination of MHC binding is obviously essential prior to making conclusions as to the effect of various ligands upon TCR-pMHC interactions.. The rate at which TCR and pMHC associate (kon) and dissociate (koff) is shown. The t1/2 of the TCR-pMHC interaction is related to the off-rate koff by the equation t1/2 = ln 2/koff. Thus, shorter TCR-pMHC interactions have shorter t1/2 and faster off-rates relative to longer TCR-pMHC interactions. In equilibrium conditions, the affinity is calculated from koff/kon, which can be derived from surface plasmon resonance measurements. The t1/2 of TCR-pMHC interactions can also be measured by dissociation of fluorescently labeled pMHC tetramers (11), and the off-rates ...
After stimulation of the T cell receptor (TCR), the tyrosine residues 292 and 315 in interdomain B of the protein tyrosine kinase ZAP-70 become phosphorylated and plausibly function as docking sites for Cbl and Vav1, respectively. The two latter proteins have been suggested to serve as substrates for ZAP-70 and to fine-tune its function. To address the role of these residues in T cell development and in the function of primary T cells, we have generated mice that express ZAP-70 molecules with Tyr to Phe substitution at position 292 (Y292F) or 315 (Y315F). When analyzed in a sensitized TCR transgenic background, the ZAP-70 Y315F mutation reduced the rate of positive selection and delayed the occurrence of negative selection. Furthermore, this mutation unexpectedly affected the constitutive levels of the CD3-zeta p21 phosphoisoform. Conversely, the ZAP-70 Y292F mutation upregulated proximal events in TCR signaling and allowed more T cells to produce interleukin 2 and interferon gamma in response ...
The rupture forces and adhesion frequencies of single recognition complexes between an affinity selected peptide/MHC complex and a TCR at a murine hybridoma surface were measured using Atomic Force Microscopy. When the CD8 coreceptor is absent, the adhesion frequency depends on the nature of the peptide but the rupture force does not. When CD8 is present, no effect of the nature of the peptide is observed. CD8 is proposed to act as a time and distance lock, enabling the shorter TCR molecule to bridge the pMHC and have time to finely read the peptide. Ultimately, such experiments could help the dissection of the sequential steps by which the TCR reads the peptide/MHC complex in order to control T cell activation.
Dive into the research topics of p21(ras) function is important for T cell antigen receptor and protein kinase C regulation of nuclear factor of activated T cells. Together they form a unique fingerprint. ...
The interaction between a T cell and an antigen-presenting cell (APC) can trigger a signaling response that leads to T cell activation. Prior studies have shown that ligation of the T cell receptor (TCR) triggers a signaling cascade that proceeds through the coalescence of TCR and various signaling molecules (e.g., the kinase Lck and adaptor protein LAT [linker for T cell activation]) into microdomains on the plasma membrane. In this study, we investigated another ligand-receptor interaction (CD58-CD2) that facilities T cell activation using a model system consisting of Jurkat T cells interacting with a planar lipid bilayer that mimics an APC. We show that the binding of CD58 to CD2, in the absence of TCR activation, also induces signaling through the actin-dependent coalescence of signaling molecules (including TCR-zeta chain, Lck, and LAT) into microdomains. When simultaneously activated, TCR and CD2 initially colocalize in small microdomains but then partition into separate zones; this ...
TY - JOUR. T1 - CD161 (NKR-P1A) costimulation of CD1d-dependent activation of human T cells expressing invariant Vα24JαQT cell receptor α chains. AU - Exley, Mark. AU - Porcelli, Steven. AU - Furman, Margo. AU - Garcia, Jorge. AU - Balk, Steven. PY - 1998/9/7. Y1 - 1998/9/7. N2 - A population of human T cells expressing an invariant Vα24JαQ T cell antigen receptor (TCR) α chain and high levels of CD161 (NKR-P1A) appears to play an immunoregulatory role through production of both T helper (Th) type 1 and Th2 cytokines. Unlike other CD161+ T cells, the major histocompatibility complex-like nonpolymorphic CD1d molecule is the target for the TCR expressed by these T cells (Vα24(invt) T cells) and by the homologous murine NK1 (NKR- P1C)+ T cell population. In this report, CD161 was shown to act as a specific costimulatory molecule for TCR-mediated proliferation and cytokine secretion by Mα24(invt) T cells. However, in contrast to results in the mouse, ligation of CD161 in the absence of TCR ...
Self-reactive CD4 T cells are thought to have a central role in the pathogenesis of many chronic inflammatory human diseases. Microbial peptides can activate self-reactive T cells, but the structural basis for such crossreactivity is not well understood. The Hy.1B11 T cell receptor (TCR) originates from a patient with multiple sclerosis and recognizes the self-antigen myelin basic protein. Here we report the structural mechanism of TCR crossreactivity with two distinct peptides from human pathogens. The structures show that a single TCR residue (CDR3α F95) makes the majority of contacts with the self-peptide and both microbial peptides (66.7-80.6%) due to a highly tilted TCR-binding topology on the peptide-MHC surface. Further, a neighbouring residue located on the same TCR loop (CDR3α E98) forms an energetically critical interaction with the MHC molecule. These data show how binding by a self-reactive TCR favors crossreactivity between self and microbial antigens.
T-cell cross-reactivity is essential for effective immune surveillance, but has also been implicated as a pathway to autoimmunity. Previous studies have demonstrated that T-cell receptors (TCRs) that focus on a minimal motif within the peptide are able to facilitate a high level of T-cell cross-reactivity. However, the structural database shows that most TCRs exhibit less focussed antigen binding involving contact with more peptide residues. To further explore the structural features that allow the clonally expressed TCR to functionally engage with multiple peptide-major histocompatibility complexes (pMHCs), we examined the ILA1 CD8+ T-cell clone that responds to a peptide sequence derived from human telomerase reverse transcriptase (hTERT). The ILA1 TCR contacted its pMHC with a broad peptide-binding footprint encompassing spatially distant peptide residues. Despite the lack of focused TCR-peptide binding , the ILA1 T-cell clone was still cross-reactive. Overall, the TCR-peptide contacts ...
Adaptor proteins positively or negatively regulate the T cell receptor for antigen (TCR) signaling cascade. We report that after TCR stimulation, the inhibitory adaptor downstream of kinase (Dok)-2 and its homologue Dok-1 are involved in a multimolecular complex including the lipid phosphatase Src homology 2 domain-containing inositol polyphosphate 5-phosphatase (SHIP)-1 and Grb-2 which interacts with the membrane signaling scaffold linker for activation of T cells (LAT). Knockdown of LAT and SHIP-1 expression indicated that SHIP-1 favored recruitment of Dok-2 to LAT. Knockdown of Dok-2 and Dok-1 revealed their negative control on Akt and, unexpectedly, on Zap-70 activation. Our findings support the view that Dok-1 and -2 are critical elements of a LAT-dependent negative feedback loop that attenuates early TCR signal. Dok-1 and -2 may therefore exert a critical role in shaping the immune response and as gatekeepers for T cell tolerance.
One of the most well-known among these alternative types of immunotherapies is gene modified T cell receptor (TCR) therapy. In CAR-T therapy, naturally occurring T cells are engineered to express chimeric receptors on their cell surface. The external portion of these artificial receptors is made up of an antibody that directs the T cells to recognise specific cancer cells. Like CAR-T therapy, gene modified TCR therapy also works by redirecting T cells to target tumours. However, instead of engineering T cells to have artificial chimeric receptors, gene modified TCR therapy uses genetic modification to create T cells that contain a specific T cell receptor. Gene modified TCRs can recognise antigens that are present on the inside of cancer cells (and which are presented on the cell surface by the major histocompatibility complex (MHC)). In contrast, CAR-T cells can only recognise antigens that are expressed on the cell surface.. There are many researchers and companies exploring gene modified TCR ...
ABSTRACT. Novel aspects of T cells containing TCRVβ20-1 are numerous, ranging from pathogen specific reactivity to specific tissue homing, or possible T cell subsets. Recently, it was demonstrated that TCR itself could become reactive by binding to small molecules free of the pHLA interface. Our work here was to identify a natural ligand binding to an identified pocket on the CDR2β loop of these TCR. Using docking of suspected ligands, we were able to show Guanine and Adenine diand tri-nucleotides readily bind to the identified site. Comparing these with small molecule sites found on other TCR types, we show this interaction is novel. With further molecular dynamic simulations, these sites are shown to be plausible by conducting simple computational based solubility tests as cross validation. Combined with simple proliferative responses, the identified nucleotides are also shown to have functional consequences by inducing T cell proliferation for CD4/Vβ20-1 + T cells, while failing to induce ...
This research study is being carried out to study a new way to possibly treat HIV. T‐cells are one of the white blood cells used by the body to fight HIV. CD8 T‐cells are a type of T‐cell used by the body to detect and kill cells which have been infected by foreign viruses or organisms, including the HIV virus. CD8 T‐cells must identify the HIV virus in order to kill it. Because HIV is constantly changing the way it looks to the CD8 T‐cells, some of the HIV virus escapes detection and is not killed by the CD8 T‐cells.. This research study uses a T cell receptor (TCR) protein specific for HIV (SL9 TCR) and adds it to the CD8 T‐cells in the laboratory in order to help the CD8 T‐cells recognize the constantly changing HIV virus and make it able to fight HIV more efficiently. TCR stands for T cell receptor. TCRs are found on the surface of T cells and allow the T cells to recognize other cells. Laboratory studies have shown that when CD8 T‐cells are modified with SL9 TCRs, they ...
About ACTolog® T-cell therapy. The ACTolog® concept is based on the principle of endogenous T-cell therapy pioneered by Professor Cassian Yee, M.D. Unlike tumor-infiltrating lymphocytes, ACTolog® T-cell products are generated from peripheral blood cells with defined target selectivity. Utilizing its proprietary antigen discovery platform XPRESIDENT®, Immatics has created a warehouse of eight cancer targets. From this warehouse, the most suitable targets for each patients tumor are identified by analyzing the tumor biomarkers. Up to four personalized T-cell products are then activated and manufactured for each patient by isolation and enrichment of the patients endogenous T-cells in vitro. Billions of such activated and specific T-cells are then re-infused into the cancer patient to attack the tumor.. About ACTengine® T-cell therapy. The ACTengine® approach is based on genetically engineering a patients own T-cells to express an exogenous T-cell receptor (TCR) to recognize the cancer ...
In adaptive immune responses, T-cell receptor (TCR) signaling impacts multiple cellular processes and results in T-cell differentiation, proliferation, and cytokine production. Although individual protein-protein interactions and phosphorylation events have been studied extensively, we lack a systems-level understanding of how these components cooperate to control signaling dynamics, especially during the crucial first seconds of stimulation. Here, we used quantitative proteomics to characterize reshaping of the T-cell phosphoproteome in response to TCR/CD28 co-stimulation, and found that diverse dynamic patterns emerge within seconds. We detected phosphorylation dynamics as early as 5 s and observed widespread regulation of key TCR signaling proteins by 30 s. Development of a computational model pointed to the presence of novel regulatory mechanisms controlling phosphorylation of sites with central roles in TCR signaling. The model was used to generate predictions suggesting unexpected roles ...
Fingerprint Dive into the research topics of RNase H-dependent PCR-enabled T-cell receptor sequencing for highly specific and efficient targeted sequencing of T-cell receptor mRNA for single-cell and repertoire analysis. Together they form a unique fingerprint. ...
We record that individual T cells persistently contaminated with primate foamy pathogen type 1 (PFV-1) display an elevated capacity to bind individual immunodeficiency pathogen type 1 (HIV-1), leading to improved cell permissiveness to HIV-1 infection and improved cell-to-cell pathogen transmission. replication could be modulated by the current presence of either homologous faulty viral genomes or infections of specific classes with the capacity of interfering with particular levels of the pathogen routine in dually contaminated organisms. It really is set up that coinfection with various other retroviruses (individual T-cell leukemia pathogen types 1 and 2) (31), individual herpesviruses (individual herpesvirus type 6 [HHV-6], HHV-7, and HHV-8) (4, 7, 9, 12, 32), or non-pathogenic flavivirus GB pathogen (30) influences development of individual immunodeficiency pathogen type 1 (HIV-1) disease. Foamy infections (FVs) are innocuous complicated retroviruses that create lifelong persistent ...
Themis and T cell development. CD4+ and CD8+ T cells expressing αβ TCRs begin their development as double negative (DN; CD4-CD8-) precursor thymocytes (Figure 6). Differentiation proceeds through several stages known as DN1-4. Progression and expansion past DN3 (CD44-CD25+) requires surface expression of the product of a chromosomally rearranged TCRβ chain, which pairs with an invariant pre-TCRα chain and then forms a complex with a CD3 heterodimer (CD3εγ or CD3εδ; see the record for tumormouse) and a CD3 zeta (ζ) homodimer (see the record for allia) (14). This complex, known as the pre-TCR, produces a TCR-like signal that is necessary for continued survival as well as the expansion of cell numbers and continued differentiation to the double positive (DP; CD4+CD8+) stage; TCR-associated signaling is described in more detail, below (15;16). After TCRβ rearrangement, progression to the DP stage, and TCRα rearrangement, the yet immature TCRαβ+CD4+CD8+ thymocytes are then subjected to ...
Anti-CD4 monoclonal antibodies are potential therapeutic agents for the prevention of autoimmune disease and treatment of rejection after organ transplantation and are capable of both restoring tolerance to self-antigens and inducing tolerance to antigens introduced under the cover of the antibody therapy in vivo. Tolerance to donor alloantigens can be induced in vivo by administering donor alloantigen in combination with either depleting (YTA 3.1) or nondepleting (YTS 177) anti-CD4, 28 days before heart transplantation in the mouse. The effect of anti-CD4 on proximal T-cell receptor (TCR) signalling pathways and proliferation was investigated in vitro and in vivo in the presence and absence of YTA 3.1 or YTS 177. Anti-CD4 was found to perturb proximal signalling events upon TCR/CD3 ligation, resulting in reduced tyrosine phosphorylation of Zap-70 and LAT (linker for activation of T cells) and reduced association of tyrosine-phosphorylated LAT with lck. This ultimately resulted in severely reduced
Adaptive immune responses often begin with the formation of a molecular complex between a T-cell receptor (TCR) and a peptide antigen bound to a major histocompatibility complex (MHC) molecule. These complexes are highly variable, however, due to the polymorphism of MHC genes, the random, inexact recombination of TCR gene segments, and the vast array of possible self and pathogen peptide antigens. As a result, it has been very difficult to comprehensively study the TCR repertoire or identify and track more than a few antigen-specific T cells in mice or humans. For mouse studies, this had led to a reliance on model antigens and TCR transgenes. The study of limited human clinical samples, in contrast, requires techniques that can simultaneously survey TCR phenotype and function, and TCR reactivity to many T-cell epitopes. Thanks to recent advances in single-cell and cytometry methodologies, as well as high-throughput sequencing of the TCR repertoire, we now have or will soon have the tools needed ...
T-Cell Receptor Signaling Phospho-Specific Array includes 188 highly specific and well-characterized phosphorylation antibodies in the T-cell receptor signaling pathway. (AA0040) - Products - Abnova
... a kind of Fc receptor called FcεRI) on the surface of other kinds of immune cells called mast cells and basophils, which are ... 1 - antigen. 2 - IgE antibody. 3 - FcεRI receptor. 4 - preformed mediators (histamine, proteases, chemokines, heparin). 5 - ... Cross-linking of the IgE and Fc receptors occurs when more than one IgE-receptor complex interacts with the same allergenic ... causes a response in a type of immune cell called a TH2 lymphocyte, which belongs to a subset of T cells that produce a ...
IgE can upregulate the expression of both types of Fcε receptors. FcεRI is expressed on mast cells, basophils, and the antigen- ... Receptors[edit]. IgE primes the IgE-mediated allergic response by binding to Fc receptors found on the surface of mast cells ... receptor FcεRII, or CD23.[23] CD23 may also allow facilitated antigen presentation, an IgE-dependent mechanism whereby B cells ... presenting dendritic cells in both mice and humans. Binding of antigens to IgE already bound by the FcεRI on mast cells causes ...
Non-expression of Duffy antigen on red cells Miller, et al. 1976 P. vivax Non-expression of Duffy antigen on red cells Miller ... Gerbich antigen receptor negativity[edit]. Main article: Gerbich antigen system. The Gerbich antigen system is an integral ... Sickle-cell[edit]. Main article: Sickle-cell anemia. See also: Sickle-cell trait and Evolutionary_baggage § Sickle-Cell and ... Duffy antigen receptor negativity[edit]. Main article: Duffy antigen system. Plasmodium vivax has a wide distribution in ...
Weiss A, Littman DR (January 1994). "Signal transduction by lymphocyte antigen receptors". Cell. 76 (2): 263-74. doi:10.1016/ ... These immune cells include T cells, B cells, NK cells, dendritic cells, macrophages and mast cells. ITIMs have similar ... the activating NK cell receptor NKp44 contains an ITIM, but this seems to be non-functional. Some of the important receptors ... containing receptors, resulting in an innate inhibition mechanism within cells. ITIM bearing receptors have important role in ...
Kurosaki T (1999). "Genetic analysis of B cell antigen receptor signaling". Annu. Rev. Immunol. 17 (1): 555-92. doi:10.1146/ ... protein encoded by this gene functions as a docking protein acting downstream of Tec tyrosine kinase in B cell antigen receptor ... A mouse ortholog, stem cell adaptor protein 1, shares 83% identity with its human counterpart. STAP1 has been shown to interact ... the stem-cell-specific adaptor protein containing PH and SH2 domains". Biochem Biophys Res Commun. 268 (3): 697-703. doi: ...
A5 antigen (a developmentally-regulated cell surface protein; Xenopus nrp1; P28824); and receptor-like tyrosine protein ... It is an extracellular domain found in many receptors. A 170 amino acid domain, the so-called MAM (meprin, A-5 protein, and ... Takagi S, Hirata T, Agata K, Eguchi G, Fujisawa H, Mochii M (1991). "The A5 antigen, a candidate for the neuronal recognition ... These proteins have a modular, receptor-like architecture comprising a signal peptide, an N-terminal extracellular domain, a ...
2005). "Ligands for natural killer cell-activating receptors are expressed upon the maturation of normal myelomonocytic cells ... Tissue Antigens. 58 (4): 255-8. doi:10.1034/j.1399-0039.2001.580406.x. PMID 11782277. "Entrez Gene: NCR3 natural cytotoxicity ... 2003). "Engagement of CD160 receptor by HLA-C is a triggering mechanism used by circulating natural killer (NK) cells to ... 2005). "Evidence that the cellular ligand for the human NK cell activation receptor NKp30 is not a heparan sulfate ...
"Structural and functional characterization of a novel T cell receptor co-regulatory protein complex, CD97-CD55". The Journal of ... Eichler W, Hamann J, Aust G (Nov 1997). "Expression characteristics of the human CD97 antigen". Tissue Antigens. 50 (5): 429-38 ... CD97 is widely expressed on, among others, hematopoietic stem and progenitor cells, immune cells, epithelial cells, muscle ... Aust G, Wandel E, Boltze C, Sittig D, Schütz A, Horn LC, Wobus M (Apr 2006). "Diversity of CD97 in smooth muscle cells". Cell ...
TSH receptor antibodies[edit]. The thyrotropin receptor (TSH receptor) is the antigen for TSH receptor antibodies (TRAbs). It ... These B-cells produce antibodies specific to the thyroid antigens. In Hashimoto's thyroiditis, activated CD4+ T-cells produce ... The production of antibodies in Graves' disease is thought to arise by activation of CD4+ T-cells, followed by B-cell ... They cause thyroid cell damage by complement activation and antibody dependent cell cytotoxicity.[7] However, anti-TPO ...
Davis, Mark M.; Bjorkman, Pamela J. (1988). "T-cell antigen receptor genes and T-cell recognition". Nature. 334 (6181): 395-402 ... Davis is well known for identifying the first T-cell receptor genes, which are responsible for T lymphocytes ability to "see" ... "2021 Szent-Györgyi Prize Awarded to Pioneering Research Duo Who Have Paved the Path to Life-Saving T-Cell Receptor-Based Cancer ... the demonstration that T cells are able to detect and respond to even a single molecule of their ligand-fragments of antigens ...
CD44 antigen, the main cell surface receptor for HA. Hyaladherin "Link domain signature and profile". PROSITE. December 2004. ... which may be involved in cell-cell and cell-matrix interactions during inflammation and tumourigenesis; ... a hyaluronan-binding domain involved in extracellular matrix stability and cell migration". Cell. 86 (5): 767-75. doi:10.1016/ ... It is important in blood cell migration and apoptosis. The link domain is found in some extracellular proteins in vertebrates ...
As a variable cell surface receptor on immune cells, these D antigens, originally HL-A4 antigens, are involved in graft versus ... class II receptor/antigens to a great many T-cells, each with unique T-cell receptor (TCR) variants. A few TCR variants that ... HLA-DQ (DQ) is a cell surface receptor protein found on antigen presenting cells. It is an αβ heterodimer of type MHC class II ... HLA DQ functions as a cell surface receptor for foreign or self antigens. The immune system surveys antigens for foreign ...
Human Antibodies Against Cell Surface Tumor Antigens Selected From Repertoires Displayed on T Cell Chimeric Antigen Receptors ... The process as a whole results in an effector cell, typically a T-cell, that can recognize a tumor cell antigen in a manner ... cytotoxic proteins and proliferation of T cells to kill CD19 B cells. Chimeric antigen receptors (CARs) have been developed as ... T cells purified from each person are modified by a virus that inserts genes that encode a chimaeric antigen receptor into ...
Patel, K.J.; Neuberger, M.S. (1993). "Antigen presentation by the B cell antigen receptor is driven by the αβ sheath and occurs ... Patel, Ketan Jayakrishna (1994). Antigen presentation by the B cell antigen receptor (PhD thesis). University of Cambridge. ... Such crosslinks are lethal to cells since they would prevent DNA from being copied (DNA replication) or for the genes it ... Patel's research is mainly concerned with how living cells repair DNA crosslinks. These lesions cause the two opposing strands ...
"The B-cell antigen receptor of the five immunoglobulin classes". Nature. 352 (6338): 777-81. Bibcode:1991Natur.352..777V. doi: ... Cell. 36 (3): 681-8. doi:10.1016/0092-8674(84)90348-9. PMID 6421489. S2CID 54312675. Ellison J, Hood L (Mar 1982). "Linkage and ... Cell. 29 (2): 691-9. doi:10.1016/0092-8674(82)90185-4. PMID 6288268. S2CID 54345379. Ellison J, Buxbaum J, Hood L (1983). " ... "Cloning and sequence determination of the gene for the human immunoglobulin epsilon chain expressed in a myeloma cell line". ...
... as effector cells for antibody-mediated killing via CD16 modified cells and as effector cells for chimeric antigen receptor ( ... NK-92 cells can be genetically engineered to recognize and kill human cancer cells. Chimeric Antigen Receptor (CAR) engineered ... NK-92 cells, like blood NK cells, can attack cancer cells if the tumor has not grown out of control. NK-92 cells were isolated ... Porter DL, Levine BL, Kalos M, Bagg A, June CH (August 2011). "Chimeric antigen receptor-modified T cells in chronic lymphoid ...
"Actin restricts FcɛRI diffusion and facilitates antigen-induced receptor immobilization". Nature Cell Biology. 10 (8): 955-963 ... Meanwhile, the formation of engaged receptor clusters might lead to de novo polymerization of actin filaments at the receptor ... Kusumi A, Sako Y (August 1996). "Cell surface organization by the membrane skeleton". Current Opinion in Cell Biology. 8 (4): ... Receptor monomers can hop across the inter-compartment boundaries quite readily, but when they form oligomers, their size ...
"Chimeric Antigen Receptor-Modified T Cells in Chronic Lymphoid Leukemia". New England Journal of Medicine. 365 (8): 725-733. ... American cell phone service provider Sprint Nextel reportedly pays $20 billion for rights to Apple's next mobile phone. October ... January 20 - In a landmark study that will ultimately see the cure for AIDS, a new technique renders T-Cells resistant to HIV. ... The United States Department of Justice files a lawsuit in an attempt to stop the $39 billion merger between cell phone giants ...
... and KIR2DL4 in antigen presenting cells, NK cells, and T cells". FASEB J. 19 (6): 662-4. doi:10.1096/fj.04-1617fje. PMID ... 2002). "Tolerization of dendritic cells by T(S) cells: the crucial role of inhibitory receptors ILT3 and ILT4". Nat. Immunol. 3 ... "Isotypic variation of novel immunoglobulin-like transcript/killer cell inhibitory receptor loci in the leukocyte receptor ... The receptor can also function in antigen capture and presentation. It is thought to control inflammatory responses and ...
McGreal E, Miller J, Gordon S (2005). "Ligand recognition by antigen-presenting cell C-type lectin receptors". Curr Opin ... a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells". Cell. 100 (5): 587-97. doi:10.1016/ ... DC-SIGN is a C-type lectin receptor present on the surface of both macrophages and dendritic cells. DC-SIGN on macrophages ... Cambi A, Figdor CG (2004). "Dual function of C-type lectin-like receptors in the immune system". Curr. Opin. Cell Biol. 15 (5 ...
... that prevents T-cell activation and proliferation by binding the T-cell receptor complex present on all differentiated T cells ... The IL-2a (CD25, T-cell activation antigen, TAC) is expressed only by the already-activated T lymphocytes. Therefore, it is of ... causing B cells to express smaller amounts of IL-2 and IL-2 receptors. This diminishes both B cell clone expansion and antibody ... T-cell receptor directed antibodies[edit]. Muromonab-CD3 is a murine anti-CD3 monoclonal antibody of the IgG2a type ...
Ruland J, Duncan GS, Wakeham A, Mak TW (2003). "Differential requirement for Malt1 in T and B cell antigen receptor signaling ... Fc-epsilon receptor signaling pathway. • T cell proliferation. • B cell activation. • response to fungus. • positive regulation ... "T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20". Nature ... helper T cells regulates immune activation". Cell. 153 (5): 1036-49. doi:10.1016/j.cell.2013.04.034. PMID 23706741.. ...
"Association of SWAP-70 with the B cell antigen receptor complex". Proc. Natl. Acad. Sci. U.S.A. 97 (5): 2180-4. doi:10.1073/ ... 1992). "Crystal structure of a chimeric Fab' fragment of an antibody binding tumour cells". J. Mol. Biol. 227 (1): 253-64. doi: ... 1982). "Structure of human immunoglobulin gamma genes: implications for evolution of a gene family". Cell. 29 (2): 671-9. doi: ...
... that are rearranged during the development of the lymphocyte to provide that cell with a unique antigen receptor. The T cell ... B cell receptor T cell receptor Basel Institute for Immunology Charles M. Steinberg NKT cell Recombination-activating gene "The ... Most T-cell receptors are composed of a variable alpha chain and a beta chain. The T cell receptor genes are similar to ... V(D)J recombination allows for the generation of immunoglobulins and T cell receptors to antigens that neither the organism nor ...
... with Androgen receptor variant expression similar to that of AR-V7High VCaP cells. Notably, LN95 cells are significantly more ... LNCaP cells also express Prostate Specific Antigen (PSA). In vivo, Male mice develop tumors earlier and at a greater frequency ... LNCaP cells are a cell line of human cells commonly used in the field of oncology. LNCaP cells are androgen-sensitive human ... C4-2B cells produce and retain approximately 8x more mineralized calcium than parental LNCaP cells. C4-2B cells also express ...
2005). "Investigation of killer cell immunoglobulin-like receptor gene diversity V. KIR3DL2". Tissue Antigens. 64 (3): 226-34. ... Killer cell immunoglobulin-like receptor 3DL2 is a protein that in humans is encoded by the KIR3DL2 gene. Killer cell ... 2000). "Diversity of the p70 killer cell inhibitory receptor (KIR3DL) family members in a single individual". Mol. Cells. 10 (1 ... "The natural killer cell receptor specific for HLA-A allotypes: a novel member of the p58/p70 family of inhibitory receptors ...
Induction of T-cell anergy by altered T-cell-receptor ligand on live antigen-presenting cells. Nature. 363(6425): pgs. 156-159 ... He and Emil R. Unanue were responsible for the discovery that antigen-presenting cells present antigens to bind to a special ... 1601-1608 Kersh EN, Shaw AS, Allen PM (1998). Fidelity of T cell activation through multistep T cell receptor ζ phosphorylation ... Separation of IL-4 production from Th cell proliferation by an altered T cell receptor ligand. Science. 252(5010): pgs. 1308- ...
"Association between killer-cell immunoglobulin-like receptor genotypes and leprosy in Brazil". Tissue Antigens. 72 (5): 478-82 ... Killer cell immunoglobulin-like receptors (KIRs) are transmembrane glycoproteins expressed by natural killer cells and subsets ... Killer cell immunoglobulin-like receptor, two domains, short cytoplasmic tail, 1 is a protein that in humans is encoded by the ... "Entrez Gene: Killer cell immunoglobulin-like receptor, two domains, short cytoplasmic tail, 1". Kimoto Y, Horiuchi T, Tsukamoto ...
It downregulates the B cell receptor.. *It induces apoptosis of CD20+ cells. ... It increases MHC II and adhesion molecules LFA-1 and LFA-3 (lymphocyte function-associated antigen). ... cells in destroying these B cells. When an NK cell latched onto the cap, it had an 80% success rate at killing the cell. In ... The antibody binds to the cell surface protein CD20. CD20 is widely expressed on B cells, from early pre-B cells to later in ...
... and internalizes offending antigens, which are taken up by the B cell through receptor-mediated endocytosis and processed. ... Plasma cells, also called plasma B cells, plasmocytes, plasmacytes, or effector B cells, are white blood cells that secrete ... In humans, CD27 is a good marker for plasma cells, naive B cells are CD27-, memory B-cells are CD27+ and plasma cells are ... Germinal center B cells may differentiate into memory B cells or plasma cells. Most of these B cells will become plasmablasts ( ...
MR1 antigen presentation to mucosal-associated invariant T cells was highly conserved in evolution. Proceedings of the National ... Neonatal and adult recent thymic emigrants produce IL-8 and express complement receptors CR1 and CR2. JCI insight. 2017-08-17, ... T Cells to protect tumour cells. Nature Communications. March 2018, 9 (1): 948. PMC 5838096. PMID 29507342. doi:10.1038/s41467- ... 细胞毒性T细胞(CTLs, killer T cells)负责杀伤被病毒感染的细胞和癌细胞,在对器官移植的
β-catenin is particularly interesting as it plays a dual role in the cell. First of all, by binding to cadherin receptor ... Peyriéras N, Louvard D, Jacob F (December 1985). "Characterization of antigens recognized by monoclonal and polyclonal ... F9 embryonal carcinoma cells are similar to the P19 cells shown in Figure 1 and normally have cell-to-cell adhesion mediated by ... A tumor cell line with defective δ-catenin, low levels of E-cadherin and poor cell-to-cell adhesion could be restored to normal ...
The TH2 lymphocytes interact with B cells and together they produce IgE. IgE circulates around and binds to receptors of cells ... the Antigen-Presenting Cell causes a response in a TH2 lymphocyte which produce the cytokine interleukin-4 (IL-4). ... Collingridge GL, Isaac JT, Wang YT (2004). "Receptor trafficking and synaptic plasticity". Nat Rev Neurosci 5(12): 952-962, ... The neural basis of behavioral sensitization is often not known, but it typically seems to result from a cellular receptor ...
When a cell is infected with EBOV, receptors located in the cell's cytosol (such as RIG-I and MDA5) or outside of the cytosol ( ... "First Antigen Rapid Test for Ebola through Emergency Assessment and Eligible for Procurement". World Health Organization (WHO ... dendritic cells and other cells including liver cells, fibroblasts, and adrenal gland cells.[93] Viral replication triggers ... doi:10.1016/j.cell.2014.10.006. PMC 4243531. PMID 25417101.. *^ a b c d e f g h Kühl A, Pöhlmann S (September 2012). "How Ebola ...
Δ32 homozygous individual with two genetic copies of a rare variant of a cell surface receptor. This genetic trait confers ... for human leukocyte antigen (HLA) matching (see PGD for HLA matching) in order to donate to an ill sibling requiring HSCT. ... who have lost their stem cells after birth. Other conditions[13] treated with stem cell transplants include sickle-cell disease ... Peripheral blood stem cells[26] are now the most common source of stem cells for HSCT. They are collected from the blood ...
"Expression of apolipoprotein C-IV is regulated by Ku antigen/peroxisome proliferator-activated receptor gamma complex and ... A critical role for nuclear liver X receptors alpha and beta". J. Biol. Chem. 277 (35): 31900-8. doi:10.1074/jbc.M202993200. ... Cell surface receptors. *HDL: SCARB1. *IDL: LRP *LRP1. *LRP1B. *LRP2. *LRP3. *LRP4 ...
The spirochetes may also induce host cells to secrete quinolinic acid, which stimulates the NMDA receptor on nerve cells, which ... The CDC does not recommend urine antigen tests, PCR tests on urine, immunofluorescent staining for cell-wall-deficient forms of ... OspA antigens, shed by live Borrelia bacteria into urine, are a promising technique being studied.[117] The use of nanotrap ... Within the tick midgut, the Borrelia's outer surface protein A (OspA) binds to the tick receptor for OspA, known as TROSPA. ...
"BLyS receptor signatures resolve homeostatically independent compartments among naïve and antigen-experienced B cells.". Semin ... 2000). "Characterization of a new member of the TNF family expressed on antigen presenting cells.". Biol. Chem. 380 (12): 1443- ... 2000). "TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease.". Nature 404 (6781): 995-9. ... "B cell maturation protein is a receptor for the tumor necrosis factor family member TALL-1". Proc. Natl. Acad. Sci. U.S.A. 97 ( ...
... and anti-acetylcholine receptor antibodies in myasthenia gravis". Tissue Antigens. 12 (5): 381-6. doi:10.1111/j.1399-0039.1978. ... In 1975, association with "HL-A1,8" (Current name: HLA A1-B8) was confirmed by serological typing of cells from myasthenics.[11 ... "Correlation between acetylcholine receptor antibody titer and HLA-B8 and HLA-DRw3 antigens in myasthenia gravis". Trans Am ... "Tissue Antigens. 64 (5): 575-80. doi:10.1111/j.1399-0039.2004.00310.x. PMID 15496200.. ...
They attach to the cell surfaces via specific receptors and are taken up by an endosomal vesicle. Inside the endosome, the ... Liver biopsy can verify inflammation and necrosis of hepatocytes and detect viral antigens. Because of the bleeding tendency of ... Receptor binding, as well as membrane fusion, are catalyzed by the protein E, which changes its conformation at low pH, causing ... After entering the host cell, the viral genome is replicated in the rough endoplasmic reticulum (ER) and in the so-called ...
... capabilities diminished capacity to produce effector lymphokines shrinkage of antigen-recognition repertoire of T-cell receptor ... The cytotoxicity of Natural Killer (NK) cells and the antigen-presenting function of dendritic cells is known to diminish with ... "Age-associated accumulation of CMV-specific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1 ... "Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1)". ...
Another system, cellular immunity, is done in the tissues by cells. *↑ Pier GB, Lyczak JB, Wetzler LM (2004). Immunology, ... Nemazee D (2006). "Receptor editing in lymphocyte development and central tolerance". Nat Rev Immunol 6 (10): 728-40. doi: ... The antibody recognizes a unique part of the foreign target called an antigen.[1][2] Each tip of the "Y" of an antibody ... Using this binding mechanism, an antibody can tag a microbe or an infected cell for attack by other parts of the immune system ...
Esophageal squamous cell cancer. Over-expression. 47%. Immunohistochemistry. [24]. Renal cell carcinoma. Under-expression. 100% ... Breast cancer (progesteron receptor negative). Over-expression. -. messenger RNA. [16]. Breast cancer. Under-expression. 30%. ... "Association of BRCA1 with Rad51 in mitotic and meiotic cells". Cell. 88 (2): 265-75. doi:10.1016/s0092-8674(00)81847-4. PMID ... Non-small-cell lung cancer. Over-expression. 29%. Immunohistochemistry. [22]. Soft tissue sarcoma. Over-expression. 95%. ...
"Molecular cloning of the CD2 antigen, the T-cell erythrocyte receptor, by a rapid immunoselection procedure.". Proc. Natl. ... 1986). "The sheep erythrocyte receptor and both alpha and beta chains of the human T-lymphocyte antigen receptor bind the ... Peterson A, Seed B (1987). "Monoclonal antibody and ligand binding sites of the T cell erythrocyte receptor (CD2).". Nature 329 ... Tamén recibiu o nome de antíxeno de superficie de células T T11/Leu-5, LFA-2, receptor LFA-3, receptor de eritrocitos e ...
"M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy". The New England Journal of Medicine. ... This, in turn, stimulates release of proteases and oxidants by the mesangial and epithelial cells, damaging the capillary walls ... The immune complexes are formed by binding of antibodies to antigens in the glomerular basement membrane. The antigens may be ... One study has identified antibodies to an M-type phospholipase A2 receptor in 70% (26 of 37) cases evaluated.[2] In 2014, a ...
... uses serotonin receptors to infect cells". Science. 306 (5700): 1380-3. doi:10.1126/science.1103492. PMID 15550673.. CS1 maint ... A map of the genome of JC virus, indicating the position of the tumor antigen genes (red), the three capsid protein genes ( ... Follicular dendritic cell sarcoma. Extranodal NK/T-cell lymphoma, nasal type. MCPyV Merkel-cell carcinoma. RNA virus. HCV ... For example, JCV has been found to infect the granule cell layer of the cerebellum, while sparing purkinje fibers, ultimately ...
Pulendran B, Ono SJ (2008). "A shot in the arm for mast cells". Nat. Med. 14 (5): 489-490. doi:10.1038/nm0508-489. PMID ... Vezava IgE na ta receptor je nepovratna in tako se površina mastocita obda z nase vezanimi IgE. IgE so proizvod plazmatk in so ... Alergen se veže na antigen vezavno mesto na IgE (le-ta se nahajajo na različnih predelih IgE, vezanega na površje mastocita). ... Prussin C, Metcalfe DD (2003). "IgE, mast cells, basophils, and eosinophils". J Allergy Clin Immunol. 111 (2 Suppl): S486-94. ...
FDPs, and a specific FDP, the D-dimer, can be measured using antibody-antigen technology. This is more specific than the TCT, ... ADP receptor/P2Y12 inhibitors. *Thienopyridines *Clopidogrel. *Prasugrel. *Ticlopidine. *Nucleotide/nucleoside analogs * ...
... antigen - antigen presentation - antigen-presenting cell (APC) - antineoplastic - antiprotozoal - antiretroviral drugs - ... radiology - randomized trial - rebound - receptor (immunology) - recombinant - recombinant DNA - recombinant DNA technology - ... T suppressor cells - T4 cell - T4 cells (T-helper cells) - T8 cells - Tanner staging - TAT - TB - template - TeachAIDS - ... B-cell lymphoma - B cells - B lymphocytes (B cells) - bactericidal - bacteriostatic - bacterium - baculovirus - baseline - ...
CD8+ cytotoxic T cells: T cells displaying co-receptor CD8 are known as CD8+ T cells. These cells bind antigens presented on ... T cells: *CD4+ helper T cells: T cells displaying co-receptor CD4 are known as CD4+ T cells. These cells have T-cell receptors ... Nearly all nucleated cells display MHC I.. *γδ T cells possess an alternative T cell receptor (different from the αβ TCR found ... B cells: releases antibodies and assists activation of T cells. *T cells: *CD4+ Th (T helper) cells: activate and regulate T ...
This is carried out by using donor-derived antigen-presenting cells. These new methods have reduced culture time to 10-12 days ... interleukin 7 receptor chain α deficiency, CD45 deficiency, CD3δ/CD3ε deficiency. T-/B- SCID (both T and B cells absent): RAG 1 ... cell responses to mitogens and allogeneic cells, cytokine production by cells Tests for B cell function: antibodies to routine ... natural killer cells and monocytes (CD15+), as well as activation markers (HLA-DR, CD25, CD80 (B cells). Tests for T cell ...
... which are able to bind to a receptor protein on a host cell. There are two strands of RNA within the cell that have three ... Group-specific antigen (gag) proteins are major components of the viral capsid, which are about 2000-4000 copies per virion. ... the cell membrane degrades, becoming part of the host cell, and the RNA strands and enzymes enter the cell (3). Within the cell ... In this way some retroviruses can convert normal cells into cancer cells. Some provirus remains latent in the cell for a long ...
Jean-Pierre Changeux isolated in 1970 the first receptor to a neurotransmitter, the acetylcholine receptor. ... The phagocytosis theory is based on the notion that phagocytes are cells that have the power to englobe foreign bodies - and ... as an antigen, Richard F. J. Pfeiffer introduced it in the abdomen of a guinea pig already vaccinated against this disease, and ... In 1985, the first human vaccine obtained by genetic engineering from animal cells, the vaccine against hepatitis B, was ...
When interleukin-1 is produced in response to external stimuli, it can bind to cell-surface receptors on the same cell that ... when a T cell is induced to mature by binding to a peptide:MHC complex on a professional antigen-presenting cell and by the B7: ... Paracrine signaling is a form of cell-cell communication in which a cell produces a signal to induce changes in nearby cells, ... These T cells can then go on to perform effector functions such as macrophage activation, B cell activation, and cell-mediated ...
Dendritic cells are very important in the process of antigen presentation, and serve as a link between the innate and adaptive ... The binding of bacterial molecules to receptors on the surface of a macrophage triggers it to engulf and destroy the bacteria. ... Instead, NK cells destroy compromised host cells, such as tumor cells or virus-infected cells. It recognises such cells by a ... Mast cells[change , change source]. Main article: Mast cell. Mast cells are a type of innate immune cell in connective tissue ...
... receptor, beta. Reference[uredi - уреди , uredi izvor]. *↑ Wolff B, Burns AR, Middleton J, Rot A (November 1998 ... Yuan A, Chen JJ, Yao PL, Yang PC (2006). "The role of interleukin-8 in cancer cells and microenvironment interaction". Front. ... Primarna funkcija IL-8 citokina je da regrutuje neutrofile da fagocitoziraju antigen koji je pobudio antigenski obrazac toll- ... G-protein spregnuti receptor proteinski signalni put. • interćelijska signalizaciona kaskada. • interćelijska signalizacija. • ...
TI-1 antigens activate B-cells via Toll like receptors, which are, in human, expressed on the surface of B lymphocytes after ... TI-1 antigen[edit]. TI-1 antigens have an intrinsic B cell activating activity, that can directly cause proliferation and ... TI-1 antigen, which has an activity that can directly activate B cells and TI-2 antigen, which has highly repetitive structure ... TI-1 antigens are classified as B-cell mitogens, because they induce numerous cell divisions. In higher concentrations, TI-1 ...
... is constitutively associated with the B cell antigen receptor and phosphorylated upon receptor stimulation". J. Immunol. 157 (9 ... 2004). "NTB-A, a new activating receptor in T cells that regulates autoimmune disease". J. Biol. Chem. 279 (18): 18662-9. PMID ... Del Valle JM، Engel P، Martín M (2003). "The cell surface expression of SAP-binding receptor CD229 is regulated via its ... T-helper 17 cell lineage commitment. • regulation of immune response. • natural killer cell differentiation. ...
T-cell antigen receptors: T-cell antigen receptors are found only on the cell membrane. For this reason, T-cell receptors were ... T-cell receptors consist of two polypeptide chains. The most… ... Other articles where T-cell antigen receptor is discussed: ... T-cell antigen receptors. T-cell antigen receptors are found only on the cell membrane. For this reason, T-cell receptors were ... www.britannica.com/science/T-cell-antigen-receptor", "title": "T-cell antigen receptor", "documentGroup": "TOPIC PAGINATED ...
... are synthetic proteins expressed on the surface of T cells. These receptors have both extracellular and intracellular ... a Structurally Differentiated Chimeric Antigen Receptor T (CAR-T) Cell Therapy Targeting B-Cell Maturation Antigen (BCMA), in ... Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas. N Engl J Med. 2017 Dec 28. 377 (26):2545-2554. [Medline]. [ ... Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas. N Engl J Med. 2017 Dec 28. 377 (26):2545-2554. [Medline]. ...
Cell. 2005 Aug 12;122(3):333-6. Research Support, N.I.H., Extramural; Research Support, Non-U.S. Govt; Research Support, U.S. ... Structures of many of the cell surface receptor-ligand complexes mediating the interactions between T cells and target cells ... How the T cell receptor sees antigen--a structural view.. Garcia KC1, Adams EJ. ... While snapshots of T cell receptors bound to their peptide-MHC ligands appear to have defined a general interaction or "docking ...
Antigen-specific T-cell activation independently of the MHC: chimeric antigen receptor-redirected T cells. Front Immunol. 2013; ... Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. J Immunother ... Coexpressed catalase protects chimeric antigen receptor-redirected T cells as well as bystander cells from oxidative stress- ... Chimeric antigen receptor T cells against CD19 for multiple myeloma. N Engl J Med. 2015;373:1040-7.CrossRefPubMedPubMedCentral ...
Chimeric Antigen Receptor (CAR) T cell Immunotherapy- Competitive Landscape,... ... Chimeric Antigen Receptor (CAR) T cell Immunotherapy - Competitive Landscape, Pipeline and Market Analysis, 2017 Press Release ... DelveInsights, Chimeric Antigen Receptor (CAR) T cell Immunotherapy- Competitive Landscape, Pipeline and Market Analysis, 2017 ... Coverage of the Chimeric Antigen Receptor (CAR) T cell Immunotherapy pipeline on the basis of target, MOA, route of ...
Adoptive T-cell therapy of B-cell malignancies: conventional and physiological chimeric antigen receptors.. Liu L1, Sun M, Wang ... Adoptive T-cell therapy (ACT) using modified T cells with chimeric antigen receptors (CARs) targeted to specific tumor- ... Investigators optimized the design of CARs to enhance receptor mediated T cell signaling and demonstrated that second and third ... associated antigens expressed by B-cell malignancies represents an attractive approach for cancer immunotherapy. ...
Genomic organization of the human T-cell antigen-receptor alpha/delta locus. K Satyanarayana, S Hata, P Devlin, M G Roncarolo, ... Two clusters of overlapping cosmid clones comprising about 100 kilobases (kb) at the human T-cell antigen-receptor alpha/delta ... Genomic organization of the human T-cell antigen-receptor alpha/delta locus ... Genomic organization of the human T-cell antigen-receptor alpha/delta locus ...
T cell Immunotherapy - Competitive Landscape, Pipeline and Market Analysis, 2017 provides information on pricing,... ... Chimeric Antigen Receptor (CAR) T cell Immunotherapy Pipeline on the Basis of Target, MOA, Route of Administration, Technology ... DelveInsights, Chimeric Antigen Receptor (CAR) T cell Immunotherapy- Competitive Landscape, Pipeline and Market Analysis, 2017 ... Coverage of the Chimeric Antigen Receptor (CAR) T cell Immunotherapy pipeline on the basis of target, MOA, route of ...
However, in competition experiments only the high-affinity B cells responded to antigen. CD19 deficiency increased the affinity ... large differences in affinity produce only small differences in the intrinsic ability of B cells to respond to antigen, and ... and low-affinity B cells to NP-Ficoll was only twofold. ... Lyn deficiency enhanced clonal expansion but abrogated B cell ... To examine how B cell receptor affinity affects clonal selection in thymus-independent type 2 (TI-2) immune responses, we ...
... engagement leads to actin polymerization at the site of T cell contact with antigen-presenting cells. Here we have studied the ... were recruited to the TCR during initial T cell activation, where they colocalized with the tyrosine kinase Zap70. The ... dynamic activity of proteins involved in regulating actin polymerization in live T cells after activation. Two such adaptor ... T cell receptor (TCR) engagement leads to actin polymerization at the site of T cell contact with antigen-presenting cells. ...
T-cell antigen receptor binding sites for the microbial superantigen staphylococcal enterotoxin A.. C H Pontzer, M J Irwin, N R ... T-cell antigen receptor binding sites for the microbial superantigen staphylococcal enterotoxin A. ... T-cell antigen receptor binding sites for the microbial superantigen staphylococcal enterotoxin A. ... T-cell antigen receptor binding sites for the microbial superantigen staphylococcal enterotoxin A. ...
The successful use of chimeric antigen receptors (CARs) for the generation of antigen-specific effector T cells suggests that a ... Current methods to generate alloantigen-specific Tregs rely on expansion with allogeneic antigen-presenting cells, which ... disease-relevant antigen-specific Tregs may have numerous advantages, such as a need for fewer cells and reduced risk of ... Adoptive immunotherapy with regulatory T cells (Tregs) is a promising treatment for allograft rejection and graft-versus-host ...
... cell-based therapy for B-cell malignancies, and early phase clinical trials have been launched in recent years. The few ... Many studies have struggled to improve the clinical responses to and benefits of CART-cell treatment of solid tumors. In this ... Although antitumor effects were confirmed,i, in vitro,/i, and in animal models, CART-cell-based therapy still faces several ... Importantly, we will suggest improvements that could increase the therapeutic effectiveness of CART cells for solid tumors and ...
... each B lymphocyte contains up to 120000 B cell antigen receptor (BCR) complexes on its cell surface. How these abundant ... receptors remain silent on resting B cells and how they can be activated by a molecularly diverse set of ligands is poorly ... To detect its cognate antigen, each B lymphocyte contains up to 120000 B cell antigen receptor (BCR) complexes on its cell ... The dissociation activation model of B cell antigen receptor triggering FEBS Lett. 2010 Dec 15;584(24):4872-7. doi: 10.1016/j. ...
... including B-cell maturation antigen (BCMA), CD38, CD138, SLAMF7, and natural killer gro... more ... Several myeloma target antigens are being investigated in clinical trials of patients with R/R multiple myeloma, ... a Structurally Differentiated Chimeric Antigen Receptor T (CAR-T) Cell Therapy Targeting B-Cell Maturation Antigen (BCMA), in ... Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas. N Engl J Med. 2017 Dec 28. 377 (26):2545-2554. [Medline]. [ ...
... is a nuclear receptor acting as a transcription factor involved in the regulation of energy metabolism, cell cycle, cell ... Beyond CAR-T cells: Natural killer cells immunotherapy.. Authors: Corral Sánchez MD, Fernández Casanova L, Pérez-Martínez A ... Donor-Derived CD123-Targeted CAR T Cell Serves as a RIC Regimen for Haploidentical Transplantation in a Patient With FUS-ERG+ ... Curing Ph+ ALL: assessing the relative contributions of chemotherapy, TKIs, and allogeneic stem cell transplant. ...
T-cell immunotherapy has gained significant attention in the past decade due to its considerable potential in the treatment of ... Fluorescent antigen-transfected target cell cytotoxic T lymphocyte assay for ex vivo detection of antigen-specific cell- ... Chimeric antigen receptor (CAR) T cell therapy for malignant cancers: summary and perspective. J Cell Immunother. 2016;2(2):59- ... Chimeric antigen receptor T cells for cancer immunotherapy. J Clin Oncol. 2015;33(15):1703-6.CrossRefGoogle Scholar ...
The advent of CAR T‐cell therapy has seen significant improvements in survival and is a potential cure for patients with ...
... and offer our perspective on how expanding the use of CAR T cells in solid tumors may require modifications in CAR T cell ... and offer our perspective on how expanding the use of CAR T cells in solid tumors may require modifications in CAR T cell ... Although CAR T cell therapy has made remarkable strides in the treatment of patients with certain hematological cancers, in ... Although CAR T cell therapy has made remarkable strides in the treatment of patients with certain hematological cancers, in ...
... 02.09.2015 ... tumor cells but not of CD30+ healthy cells like hematopoietic stem cells. Specific genetic modifications of the anti-CD30 CAR ... This approach has been tested in vitro with CD30+ hematopoietic stem cells and CD30+ tumor cells and in vivo in mice ... Im Focus: Stem cell divisions in the adult brain seen for the first time. Scientists from the University of Zurich have ...
... a cellular therapy consisting of autologous T cells transduced with an anti-CD19 chimeric antigen receptor, after myeloablative ... A patient with refractory multiple myeloma received an infusion of CTL019 cells, ... Chimeric Antigen Receptor T Cells against CD19 for Multiple Myeloma N Engl J Med. 2015 Sep 10;373(11):1040-7. doi: 10.1056/ ... a cellular therapy consisting of autologous T cells transduced with an anti-CD19 chimeric antigen receptor, after myeloablative ...
... and thus of the B-cell repertoire, is the result of very complex immunogenetic mechanisms. So, this chapter gives a brief ... T-cells during antigen priming by dendritic cells in T-cell zones [46] (comment in [47]). The Tfh cells then give survival and ... B-cell antigen receptor complex, DZ: dark zone, FDC: follicular dendritic cell, LZ: light zone, M: mantle zone, SHM: somatic ... after both T-cells and B-cells have been primed with antigen. The activated B-cells follow one of the following two fates to ...
In this blog, read about adoptive cell transfer, the process of training and expanding a patients own immune cells and placing ... Immunotherapy is a groundbreaking option because it can hypothetically target cancer cells specifically while leaving healthy ... cells intact, which can decrease the number of adverse effects associated with current treatment options. ... it back into the patient to fight the cancer with their own cells. ...
... antigens and antibodies, polypeptide hormones, and small molecules. [Roland F Beers; Edward G Bassett; Miles Laboratories.;] ... Cell receptors schema:about cell_receptors> ; # Cell receptors ... Cell receptors a schema:Intangible ;. schema:name "Cell receptors"@en ;. . ... Cell membrane receptors for viruses, antigens and antibodies, polypeptide hormones, and small molecules. Author:. Roland F ...
Viral vectors have been used to genetically modify in vitro expanded NK cells to express chimeric antigen receptors (CARs), ... A K562 cell line expressing high levels of anti-CD19 CARs was generated as a donor cell to transfer the anti-CD19 CARs onto NK ... Anti-CD19 CAR expression was observed in expanded NK cells after these cells were co-cultured for one hour with freeze/thaw- ... Acquisition of anti-CD19 CARs via trogocytosis enhanced NK cell-mediated cytotoxicity against the B-cell acute lymphoblastic ...
... both RP215 and antibodies against antigen-receptors were shown to affect more than a dozen of genes involved in cell ... which consisted mainly of these cancer cell-expressed antigen receptors. Experimental evidence has clearly indicated that ... were also found to be highly regulated by both RP215 and anti-antigen receptor antibodies. For example, RP215 and anti-antigen ... including immunoglobulins and T-cell receptors, are known to be widely expressed by cancer cells through unconfirmed mechanisms ...
Engineering γδT cells limits tonic signaling associated with chimeric antigen receptors. *View ORCID ProfileJonathan Fisher1,2 ... Engineering γδT cells limits tonic signaling associated with chimeric antigen receptors. By Jonathan Fisher, Roshan Sharma, ... Engineering γδT cells limits tonic signaling associated with chimeric antigen receptors. By Jonathan Fisher, Roshan Sharma, ... Engineering γδT cells limits tonic signaling associated with chimeric antigen receptors Message Subject. (Your Name) has ...
... cells expressing polyclonal repertoire of endogenous γδ T-cell receptors and introduced CD19-specific chimeric antigen receptor ... T-cell receptor ligation induces distinct signaling pathways in naïve vs. antigen-experienced T cells. Proc. Natl. Acad. Sci. U ... Tonic 4-1BB costimulation in chimeric antigen receptors impedes T cell survival and is vector-dependent. Cell Rep. 21, 17-26 ( ... Human T cell receptor γδ cells recognize endogenous mevalonate metabolites in tumor cells. J. Exp. Med. 197, 163-168 (2003).. ...
The interaction of the T cell receptor for antigen (TCR) with its antigen-major histocompatibility complex ligand is difficult ... Expression of T cell antigen receptor heterodimers in a lipid-linked form ... Expression of T cell antigen receptor heterodimers in a lipid-linked form ... Expression of T cell antigen receptor heterodimers in a lipid-linked form ...
Effective NY-ESO-1-specific MHC II-restricted T cell receptors from antigen-negative hosts enhance tumor regression. ... Effective NY-ESO-1-specific MHC II-restricted T cell receptors from antigen-negative hosts enhance tumor regression. ... Adoptive transfer of T cell receptor-engineered (TCR-engineered) T cells is a promising approach in cancer therapy but needs ... Here, TCRs against the tumor-associated antigen NY-ESO-1 were isolated either from human CD4+ T cells or from mice that express ...
  • DelveInsights, Chimeric Antigen Receptor (CAR) T cell Immunotherapy - Competitive Landscape, Pipeline and Market Analysis, 2017, report provides comprehensive insights about marketed and pipeline drugs across this Mechanism of action. (mynewsdesk.com)
  • Key objective of the report is to establish the understanding for all the marketed and pipeline drugs that fall under Chimeric Antigen Receptor (CAR) T cell Immunotherapy. (mynewsdesk.com)
  • This report provides information on the therapeutic development based on Chimeric Antigen Receptor (CAR) T cell Immunotherapy mechanism of action dealing with around 20+ active pipeline drugs. (mynewsdesk.com)
  • DelveInsights Report also assesses the Chimeric Antigen Receptor (CAR) T cell Immunotherapy therapeutics by Monotherapy, Combination products, Molecule type and Route of Administration. (mynewsdesk.com)
  • Adoptive T-cell therapy (ACT) using modified T cells with chimeric antigen receptors (CARs) targeted to specific tumor-associated antigens expressed by B-cell malignancies represents an attractive approach for cancer immunotherapy. (nih.gov)
  • Adoptive immunotherapy with regulatory T cells (Tregs) is a promising treatment for allograft rejection and graft-versus-host disease (GVHD). (jci.org)
  • The outcome is equally as good as for Ph- disease, and with targeted tyrosine kinase inhibitor therapies in addition to chemotherapy, the novel immunotherapy approaches, and the extension of allogeneic hematopoietic stem cell transplant (allo-HCT) to older individuals, there is the potential to exceed this outcome. (medworm.com)
  • Chimeric antigen receptor (CAR) T-cell immunotherapy has gained significant attention in the past decade due to its considerable potential in the treatment of various types of malignancies, particularly hematological. (springer.com)
  • Chimeric antigen receptor T cells for cancer immunotherapy. (springer.com)
  • Hombach A, Hombach AA, Abken H. Adoptive immunotherapy with genetically engineered T cells: modification of the IgG1 Fc 'spacer' domain in the extracellular moiety of chimeric antigen receptors avoids 'off-target' activation and unintended initiation of an innate immune response. (springer.com)
  • Adoptive cellular immunotherapy (ACT) employing engineered T lymphocytes expressing chimeric antigen receptors (CARs) has demonstrated promising antitumor effects in advanced hematologic cancers, such as relapsed or refractory acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma, supporting the translation of ACT to non-hematological malignancies. (frontiersin.org)
  • One approach to cancer immunotherapy entails genetically engineering a patient's T cells to express chimeric antigen receptors (CARs) that recognize and attack tumor cells. (frontiersin.org)
  • Natural killer (NK) cells have the capacity to target tumors and are ideal candidates for immunotherapy. (plos.org)
  • In this study, we used trogocytosis as a non-viral method to modify NK cells for immunotherapy. (plos.org)
  • Natural killer (NK) cells have the ability to recognize and eliminate tumor cells, making them ideal candidates for tumor immunotherapy [1] , [2] . (plos.org)
  • CD19 is an ideal target antigen for immunotherapy because it is expressed on nearly all leukemia cells in most patients with B-cell acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL) [13] , [14] . (plos.org)
  • The in vitro generation of T cells with defined antigen specificity by T cell receptor (TCR) gene transfer is an established method to create cells for immunotherapy. (mdc-berlin.de)
  • CAR T-cell therapy is a rapidly emerging adoptive cell transfer immunotherapy for select patients with relapsed or refractory cancers. (cms.gov)
  • We list other attractive potential targets for CAR T cell therapy for MPM, and discuss augmentation strategies of CAR T cell therapy with other forms of immunotherapy in this disease. (mdpi.com)
  • Adoptive transfer of T cells engineered to express a chimeric antigen receptor (CAR) has emerged as a powerful targeted immunotherapy, showing striking responses in highly refractory populations. (bloodjournal.org)
  • Chimeric antigen receptor T cells (also known as CAR T cells) are T cells that have been genetically engineered to produce an artificial T-cell receptor for use in immunotherapy. (wikipedia.org)
  • The premise of CAR-T immunotherapy is to modify T cells to recognize cancer cells in order to more effectively target and destroy them. (wikipedia.org)
  • These NK-CAR-iPSC-NK cells now provide standardized, targeted 'off-the-shelf' lymphocytes for anti-cancer immunotherapy. (ca.gov)
  • CAR T-cell therapy is one of a group of new treatments, called immunotherapy, that harnesses the power of the body's immune system to detect and destroy cancer cells. (berkeleywellness.com)
  • In this review, we summarize the clinical results for CAR T cells in the case of hematologic and solid tumors, along with the current developments in CAR T cell immunotherapy. (eurekaselect.com)
  • Feng Li, Tengfei Zhang, Ling Cao and Yi Zhang*, "Chimeric Antigen Receptor T Cell Based Immunotherapy for Cancer", Current Stem Cell Research & Therapy (2018) 13: 327. (eurekaselect.com)
  • In recent years, the development of tumor immunotherapy especially chimeric antigen receptor T (CAR-T) cell has shown a promising future. (springer.com)
  • Rizvi NA, Peters S. Immunotherapy for unresectable stage III nonsmall- cell lung cancer. (springer.com)
  • This new type of targeted immunotherapy merges the exquisite targeting specificity of monoclonal antibodies with the potent cytotoxicity and long-term persistence provided by cytotoxic T cells. (springermedizin.de)
  • Novel natural killer (NK) cell-directed strategies in cancer immunotherapy aim at specifically modulating the balance between NK cell receptor signals toward tumor-specific activation. (aacrjournals.org)
  • Antigen-specific 2B4ζ-expressing NK cells may be a powerful new tool for adoptive immunotherapy of leukemia and other malignancies. (aacrjournals.org)
  • In recent years, natural killer (NK) cell strategies for cancer immunotherapy have stimulated increasing interest but their clinical application has largely been restricted to the haploidentical hematopoietic stem cell transplantation setting, where natural killer immunoglobulin receptor mismatches between the donor and recipient are exploited to enhance the graft-antileukemia effect. (aacrjournals.org)
  • Adoptive cellular immunotherapy with anti CD 19 chimeric antigen receptor (CAR) T cell has changed the treatment landscape in B cell lymphomas. (medworm.com)
  • A promising and expensive type of immunotherapy, called CAR T-cell therapy, is now covered by Medicare. (medworm.com)
  • The U.S. Food and Drug Administration has approved the immunotherapy procedure for non-Hodgkin lymphoma and B-cell precursor acute lymphoblastic leukemia. (medworm.com)
  • Adoptive immunotherapy with chimeric antigen receptor (CAR)-engineered T (CART) cells can target and kill malignant cells, thereby inducing durable clinical responses in hematopoietic malignancies ( 1-3 ). (aacrjournals.org)
  • T cells infiltrating tumors have alterations in signal transduction and function (1 , 2) , which may impair the therapeutic efficacy of various forms of immunotherapy. (aacrjournals.org)
  • Recently, a new form of immunotherapy using genetically engineered chimeric antigen receptor (CAR) T-cells has been developed. (pulsus.com)
  • CD19 CAR T cell-redirected immunotherapy is an attractive option for patients with various CD19+ leukemias (e.g. (pulsus.com)
  • Its significant efficacy coupled with limited toxicities makes CD19 CAR T-cell immunotherapy an ideal treatment approach for ALL and NHL. (pulsus.com)
  • Chimeric antigen receptor (CAR) T-cell immunotherapy has revolutionized the treatment of refractory leukemias and lymphomas, but is associated with significant toxicities, namely cytokine release syndrome (CRS) and neurotoxicity. (aacrjournals.org)
  • An autologous form of cellular immunotherapy - chimeric antigen receptor (CAR) T-cell therapy - is currently under investigation. (lymphomacoalition.org)
  • There are a number of immunotherapy approaches but this article will focus on CART T-cell therapy specifically. (lymphomacoalition.org)
  • Technology could be useful for development of immunotherapy against cancer cells that lost MHC class I or MHC class I antigen presentation machinery. (roswellpark.org)
  • Adoptive T cell immunotherapy has shown promise in treating some cancers, but the challenge of isolating T cells with high avidity for tumor antigens limits large-scale applicability. (washington.edu)
  • Using a well-characterized murine model of adoptive T cell immunotherapy for established malignancy, we have demonstrated the feasibility of eliminating disseminated leukemia using T cells genetically modified by TCR gene transfer.We next examined the potential of targeting a clinically relevant tumor antigen, the transcription factor WT1, for which the expression patterns in normal and malignant cells are similar in mouse and man. (washington.edu)
  • it recognizes a specific protein on the surface of malignant cells (eg, CD19 on B-cells). (medscape.com)
  • CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. (medscape.com)
  • The response to lymphodepletion impacts PFS in patients with aggressive non-Hodgkin lymphoma treated with CD19 CAR T cells. (medscape.com)
  • Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy. (medscape.com)
  • Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. (medscape.com)
  • Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. (medscape.com)
  • End of phase I results of ZUMA-3, a phase 1/2 study of KTE-X19, anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in adult patients (pts) with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). (medscape.com)
  • CD19 deficiency increased the affinity threshold of TI-2 responses, whereas Lyn deficiency enhanced clonal expansion but abrogated B cell terminal differentiation. (nature.com)
  • For example, several groups have reported clinical trials with anti-CD19 CART cells in which favorable clinical efficacy resulted from the specific recognition and eradication of CD19-positive tumor cells [ 3 , 4 , 6 ]. (hindawi.com)
  • A patient with refractory multiple myeloma received an infusion of CTL019 cells, a cellular therapy consisting of autologous T cells transduced with an anti-CD19 chimeric antigen receptor, after myeloablative chemotherapy (melphalan, 140 mg per square meter of body-surface area) and autologous stem-cell transplantation. (nih.gov)
  • This response was achieved despite the absence of CD19 expression in 99.95% of the patient's neoplastic plasma cells. (nih.gov)
  • One example is ALL, acute lymphoblastic leukemia, where CAR T cells engineered to target CD19, a major B cell maker, were able to wipeout cancer in 90% of the patients treated in that study 1 . (biolegend.com)
  • A K562 cell line expressing high levels of anti-CD19 CARs was generated as a donor cell to transfer the anti-CD19 CARs onto NK cells via trogocytosis. (plos.org)
  • Anti-CD19 CAR expression was observed in expanded NK cells after these cells were co-cultured for one hour with freeze/thaw-treated donor cells expressing anti-CD19 CARs. (plos.org)
  • Immunofluorescence analysis confirmed the localization of the anti-CD19 CARs on the NK cell surface. (plos.org)
  • Acquisition of anti-CD19 CARs via trogocytosis enhanced NK cell-mediated cytotoxicity against the B-cell acute lymphoblastic leukemia (B-ALL) cell lines and primary B-ALL cells derived from patients. (plos.org)
  • Further, expression of anti-CD19 chimeric antigen receptors (CARs) containing 41BB and CD3ζ signal domains on NK cells enhanced the activating signals originating from CD19 antigen engagement, leading to cytotoxicity specifically against B-cell leukemia [4] . (plos.org)
  • CD19-targeting therapies employing chimeric antigen receptor (CAR) T cells are a breakthrough in cancer therapy. (mdpi.com)
  • Complete remission (CR) rates as high as 90% have been reported in children and adults with relapsed and refractory ALL treated with CAR-modified T cells targeting the B-cell-specific antigen CD19. (bloodjournal.org)
  • Chimeric antigen receptor (CAR)-modified T cells targeting CD19, the best-studied CAR T-cell therapy to date, will be discussed, with a focus on clinical trials for ALL demonstrating efficacy as well as toxicity and toxicity management. (bloodjournal.org)
  • Clinical trials in the early 2010s using second generation CARs targeting CD19, a protein expressed by normal B cells as well as B cell leukemias and lympohomas, by investigators at the NCI, University of Pennsylvania, and Memorial Sloan Kettering Cancer Center demonstrated the clinical efficacy of CAR T cell therapies and resulted in complete remissions in many heavily pre-treated patients. (wikipedia.org)
  • Patients with relapsed or refractory CD19-positive cancers experienced complete responses with no major side effects following treatment with CAR-NK cell therapy. (curetoday.com)
  • Patients with relapsed or refractory CD19-positive cancers who were treated with cord blood-derived chimeric antigen receptor (CAR) natural killer (NK)-cell therapy experienced responses without the development of major toxic effects, according to a phase 1/2 trial published in The New England Journal of Medicine . (curetoday.com)
  • The researchers genetically engineered the cells to recognize CD19, a cancer-specific target, and are reinforced with an immune signaling molecule, IL-15, that enhances the multiplication and survival of the NK cells. (curetoday.com)
  • Cherukuri A, Cheng PC, Pierce SK (2001a) The role of the CD19/CD21 complex in B-cell processing and presentation of complement-tagged antigens. (springer.com)
  • Cherukuri A, Cheng P, Sohn H, Pierce S (2001b) The CD19/CD21 complex functions to prolong B-cell antigen receptor signaling from lipid rafts. (springer.com)
  • A single-cell analysis of the preinfusion CD19 CAR product from patients with NHL demonstrated that CAR products contain polyfunctional T-cell subsets capable of deploying multiple immune programs represented by cytokines and chemokines including interferon-γ (IFN-γ), IL-17A, IL-8, and macrophage inflammatory protein 1-α. (bloodjournal.org)
  • Additionally, treatment of solid tumors with CAR-T cells has been less successful than targeting CD19-expressing tumors. (ca.gov)
  • The primary objective of this study is to determine the ability to take a patient's own cells (T lymphocytes) and grow them in the laboratory with the CD19/CD22-CAR receptor gene through a process called 'lentiviral transduction (also considered gene therapy) and growing them to large numbers to use as a treatment for hematologic cancers in children and young adults. (centerwatch.com)
  • Researchers want to see if giving modified CD19/CD22-CAR T cells to people with these cancers can attack cancer cells. (centerwatch.com)
  • To study the safety and effects of giving CD19/CD22-CAR T cells to children and young adults with B-cell cancer. (centerwatch.com)
  • Assess the safety of administering escalating doses of autologous CD19/CD22-CAR engineered T cells that meet established release specifications in children and young adults with CD19+CD22+ B cell ALL or lymphoma following a cyclophosphamide/fludarabine conditioning regimen. (centerwatch.com)
  • Patients will receive a lymphodepleting preparative regimen of fludarabine (25 mg/m^2/d x 3 on Days -4, -3, -2) and cyclophosphamide (900 mg/m^2/d x 1 on Day -2) followed by infusion of CD19/CD22-CAR T-cells on D0. (centerwatch.com)
  • Patients who are CAR pre-treated (with exception for those with an interval HSCT) will receive increased lymphodepleting preparative regimen of fludarabine (30 mg/m^2/d x 4 on Days -5, -4, -3, -2) and cyclophosphamide (600 mg/m^2/d x 2 on Days -3, -2) followed by infusion of CD19/CD22-CAR T-cells on D0. (centerwatch.com)
  • CD19 is extensively expressed on cancerous cells in B cell malignancies. (eurekaselect.com)
  • We have combined a robust T cell culture system 6 with lentiviral vector transduction of human T cells to express a CD19-specific CAR (CART-19 cells). (jcancer.org)
  • In vitro -stimulated NK cells from healthy donors and pediatric leukemia patients were gene modified with CD19 or G D2 -specific chimeric receptors containing either the T-cell receptor ζ or 2B4 endodomain alone or combined. (aacrjournals.org)
  • Typically, engineered CAR T-cells recognize CD19 specifically, a universal B-cell surface marker expressed in many forms of B-cell malignancies. (pulsus.com)
  • In fact, anti-CD19 CAR T-cell therapy has shown remarkable clinical efficacy in the treatment of these patients. (pulsus.com)
  • This review summarizes recent developments in the field of CAR T cell therapy with an emphasis on the utilization of various CD19 CAR T cell constructs in the clinical treatment of NHL and ALL. (pulsus.com)
  • These cells are engineered to react against CD19 which is on the surface of B cells. (lymphomacoalition.org)
  • The white blood cells along with the T cells are then sent to a laboratory where they are genetically modified or manipulated to react against CD19. (lymphomacoalition.org)
  • Once the reprogrammed T cells are infused into the patient's body, they expand and start looking for cancer cells that express CD19. (lymphomacoalition.org)
  • Once found, the reprogrammed T cells attach to the CD19-expressing cells and start to kill them. (lymphomacoalition.org)
  • One such agent is CTL019, a CAR-modified T-cell therapy that reacts against CD19. (lymphomacoalition.org)
  • Recently, chimeric antigen receptor (CAR) T cell therapy has shown promising results in hematological tumors and current research is going on in various solid tumors like ovarian cancer. (springer.com)
  • The few published clinical studies of CART cells in solid tumors have addressed safety and feasibility, but the clinical outcome data are limited. (hindawi.com)
  • Although antitumor effects were confirmed in vitro and in animal models, CART-cell-based therapy still faces several challenges when directed towards solid tumors, and it has been difficult to achieve the desired outcomes in clinical practice. (hindawi.com)
  • Many studies have struggled to improve the clinical responses to and benefits of CART-cell treatment of solid tumors. (hindawi.com)
  • In this review, the status quo of CART cells and their clinical applications for solid tumors will be summarized first. (hindawi.com)
  • Importantly, we will suggest improvements that could increase the therapeutic effectiveness of CART cells for solid tumors and their future clinical applications. (hindawi.com)
  • These interventions will make treatment with CART cells an effective and routine therapy for solid tumors. (hindawi.com)
  • The clinical studies of CART cells for solid tumors have begun recently. (hindawi.com)
  • Up to date, eleven studies of CART-cell therapy for solid tumors have been conducted in the past decade (Table 1 ), and thirty-five clinical trials for various solid tumors are listed at ClinicalTrials.gov ( http://www.clinicaltrials.gov ) (Figure 1 ). (hindawi.com)
  • The registered numbers of clinical trials increase annually, and a range of tumor antigens, including CEA, mesothelin, HER2, and GD2, are being targeted for various solid tumors. (hindawi.com)
  • Although CAR T cell therapy has made remarkable strides in the treatment of patients with certain hematological cancers, in solid tumors success has been limited likely due to heterogeneous antigen expression, immunosuppressive networks in the tumor microenvironment limiting CAR T cell function and persistence, and suboptimal trafficking to solid tumors. (frontiersin.org)
  • Here, we outline specific approaches to overcome barriers to CAR T cell effectiveness in the context of the tumor microenvironment and offer our perspective on how expanding the use of CAR T cells in solid tumors may require modifications in CAR T cell design. (frontiersin.org)
  • The recognition specificity of different non-self-antigens or defective self-antigens (tumors) by a well-defined B-cell clone does not result from the presence of an extensive number of receptor genes, but rather from immunogenetic mechanisms affecting a limited number of IG genes, including mechanisms of genetic recombination, mutations, deletions or insertions, and gene repair, through very complex regulatory mechanisms that are responsible for a large B-cell repertoire. (intechopen.com)
  • It was also discovered that chemotherapy and immunosuppression prior to ACT increased efficacy in these transfers, not only because of the two-pronged treatment of tumors, but also because of the elimination of old immune cells that were no longer effective at destroying tumor cells. (biolegend.com)
  • So far, many of the most promising results using CAR-transfected ACT have been observed in liquid tumors, where the cancer does not originate from a specific location, but instead a single cell type throughout the blood. (biolegend.com)
  • Viral vectors have been used to genetically modify in vitro expanded NK cells to express chimeric antigen receptors (CARs), which confer cytotoxicity against tumors. (plos.org)
  • This novel strategy could be a potential valuable therapeutic approach for the treatment of B-cell tumors. (plos.org)
  • We have previously genetically modified in vitro expanded NK cells to express DAP10 and the chimeric NKG2D receptor containing the CD3ζ signal domain, which altered the balance between the activating and inhibitory signals of NK cells and enhanced the cytotoxicity against NKG2D ligand-bearing tumors [3] . (plos.org)
  • Despite the benefits of chimeric antigen receptor (CAR)-T cell therapies against lymphoid malignancies, responses in solid tumors have been more limited and off-target toxicities have been more marked. (sciencemag.org)
  • Adoptive transfer of T cell receptor-engineered (TCR-engineered) T cells is a promising approach in cancer therapy but needs improvement for more effective treatment of solid tumors. (jci.org)
  • In addition to checkpoint blockade, adoptive T cell transfer (ACT) using chimeric antigen receptors (CARs) has shown impressive clinical outcomes in leukemias and is now being explored in solid tumors. (mdpi.com)
  • Scientists harvest T cells from people, genetically alter them, then infuse the resulting CAR-T cells into patients to attack their tumors. (wikipedia.org)
  • Once isolated from a person, these T cells are genetically engineered to express a specific CAR, which programs them to target an antigen that is present on the surface of tumors. (wikipedia.org)
  • Similar early clinical trials of CAR T cells in solid tumors in the 1990s using first generation CARs targeting a solid tumor antigens such as MUC1 did not show long term persistence of the transferred T cells or result in significant remissions. (wikipedia.org)
  • Tests of all treated patients showed that their normal B cells had been killed along with the tumors. (fightaging.org)
  • This mechanism is efficiently counteracted in many human tumors, where cells evade NK cell-mediated killing by shedding or intracellular retention of ligands for activating receptors ( 8 ). (aacrjournals.org)
  • Target-mediated toxicity is a major limitation in the development of chimeric antigen T-cell receptors (CAR) for adoptive cell therapy of solid tumors. (aacrjournals.org)
  • The use of affinity-tuned scFvs offers a strategy to empower wider use of CAR T cells against validated targets widely overexpressed on solid tumors, including those considered undruggable by this approach. (aacrjournals.org)
  • T cells infiltrating tumors have a decreased expression of signal transduction proteins, a diminished ability to proliferate, and a decreased production of cytokines. (aacrjournals.org)
  • These CAR-T cells will recognize a molecular marker on the surface of glioma cancer stem cells and kill the tumors. (ca.gov)
  • Like many tumor-associated antigens, generating robust immune responses to the WT1 protein has been difficult as endogenous WT1 expression may delete or render anergic most of the high avidity T cell repertoire capable of recognizing WT1 expressing tumors. (washington.edu)
  • However, none of the T cells isolated recognized murine tumors endogenously expressing WT1. (washington.edu)
  • We also isolated two human T cell clones specific for WT1RMFPNAPYL, one of which recognizes human tumors expressing this antigen. (washington.edu)
  • When expressed by a T cell, CARs confer antigen specificity determined by the targeting domain ( 1 , 2 ). (frontiersin.org)
  • 2003) Human epithelial cancers secrete immunoglobulin G with unidentified specificity to promote growth and survival of tumor cells. (scirp.org)
  • Christensen S, Shupe J, Nickerson K, Kashgarian M, Flavell R, Shlomchik M (2006) Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. (springer.com)
  • Specificity studies involving A and cogenic A/θAKR mice clearly demonstrated that the cell surface fluorescence and cytotoxicity produced by the antiserum is directed solely toward the θAKR alloantigen. (rupress.org)
  • Here, we show that in the antibody-mediated autoimmune disease pemphigus vulgaris (PV), autoantigen-based chimeric immunoreceptors can direct T cells to kill autoreactive B lymphocytes through the specificity of the B cell receptor (BCR). (sciencemag.org)
  • Gene transfer techniques have now been developed to genetically modify T cells to confer novel antigen specificity by stably expressing a chimeric antigen receptor (CAR) on their surface. (jcancer.org)
  • This allows the immune cells to recognize and attack cancer cells with a high degree of specificity, and the early results in the trial were impressive . (fightaging.org)
  • Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibodytype specificity. (springer.com)
  • Integration of the 2B4 endodomain into T-cell receptor ζ chimeric receptors significantly enhanced all aspects of the NK cell activation response to antigen-expressing leukemia or neuroblastoma cells, including CD25 up-regulation, secretion of IFN-γ and tumor necrosis factor-α, release of cytolytic granules, and growth inhibition, and overcame NK cell resistance of autologous leukemia cells while maintaining antigen specificity. (aacrjournals.org)
  • HLA, human leukocyte antigen. (cdc.gov)
  • After proteasomal processing, the PRAME300-309 peptide ALYVDSLFFL (ALY) is presented in the context of human leukocyte antigen HLA-A*02:01 molecules for recognition by the T cell receptor (TCR) of cytotoxic T cells. (sigmaaldrich.com)
  • Maternal killer-cell immunoglobulin-like receptors and paternal human leukocyte antigen ligands in recurrent pregnancy loss cases in Turkey. (physiciansweekly.com)
  • Compatibility between partners for human leukocyte antigen (HLA) genotypes and the relationships between maternal killer-cell immunoglobulin-like receptor (KIR) and paternal HLA-Bw4/Bw6 and HLA-C1/C2 supra-groups were investigated in 25 couples with RPL in comparison to healthy couples with children. (physiciansweekly.com)
  • Authors: Mrowka P, Glodkowska-Mrowka E Abstract Peroxisome proliferator-activated receptor-gamma (PPARγ) is a nuclear receptor acting as a transcription factor involved in the regulation of energy metabolism, cell cycle, cell differentiation, and apoptosis. (medworm.com)
  • Authors: Schultz L, Gardner R Abstract Immunotherapies have been successfully developed for the treatment of B-cell acute lymphoblastic leukemia (B-ALL) with FDA approval of blinatumomab, inotuzumab, and tisagenlecleucel for relapsed or refractory patients. (medworm.com)
  • While snapshots of T cell receptors bound to their peptide-MHC ligands appear to have defined a general interaction or "docking" solution, many of the most fundamental structural questions in antigen recognition lack detailed answers and thus pose exciting experimental challenges for the future. (nih.gov)
  • Receptor affinity and extracellular domain modifications affect tumor recognition by ROR1-specific chimeric antigen receptor T cells. (springer.com)
  • NY-ESO-1-reactive TCRs from the mice showed superior recognition of tumor cells and higher functional activity compared with TCRs from humans. (jci.org)
  • These engineered cells have the ability to identify antigens in a major histocompatibility complex (MHC)-independent manner, unlike unmodified T cells that require T cell receptor (TCR)-mediated antigen recognition. (urotoday.com)
  • CARs combine an antigen recognition domain of a specific antibody with an intracellular domain of the CD3-zeta chain or FcγRI protein into a single chimeric protein 1 . (jcancer.org)
  • CAR is an artificial antigen receptor that mediates antibody-targeted recognition. (springermedizin.de)
  • The specific recognition systems are the antibodies, capable of recognizing antigens in solution and the T lymphocytes equipped with T-cell antigen receptors (TCR) capable of recognizing internal antigens associated with the antigens of the major histocompatibility complex. (thefreedictionary.com)
  • CAR T cells trigger apoptosis in tumor targets in an MHCindependent manner upon recognition and ligation to a specific tumor associated antigen (TAA). (pulsus.com)
  • Because of their different abilities in direct recognition of cancer cells, these two types of CD4+ T cells (TR-CD4 and NTR- CD4) are considered to play different roles at the local tumor site, i.e. (roswellpark.org)
  • TR-CD4 efficiently provide CD4-help by direct recognition of cancer cells. (roswellpark.org)
  • This invention takes advantage of the fact that TR-CD4 cells provide CD4 help by direct recognition of cancer cells by using this function to provide TCR polypeptides and recombinant polynucleotides encoding them for use in novel prophylactic and/or therapeutic treatment modalities and compositions. (roswellpark.org)
  • Roswell Park Comprehensive Cancer Center is seeking partners to help co-develop compositions and methods for prophylaxis and/or therapy of cancers using T cells that have been engineered to be capable of direct recognition of tumor antigen and MHC class II expressing cancer cells. (roswellpark.org)
  • New method especially important to generate CD4+ T cells that provide efficient "CD4 help" at the local tumor site without the requirement of antigen presenting cells via direct recognition of cancer cells. (roswellpark.org)
  • We hypothesized that in vitro engineering to increase TCR affinity would improve tumor cell recognition, although the potential for such high affinity TCRs to recognize normal tissues expressing low levels of WT1 would need to be assessed.To test this hypothesis, we characterized the murine and human T cell responses elicited to WT1RMFPNAPYL. (washington.edu)
  • The TCRs from these T cells are being used as templates for in vitro mutagenesis and selection of higher affinity TCRs by yeast display to determine the threshold required for efficient tumor recognition without targeting normal tissues. (washington.edu)
  • CDR4 of the β-chain is not thought to participate in antigen recognition, but has been shown to interact with superantigens. (wikipedia.org)
  • In contrast to conventional T cell receptors (TCRs), which recognize antigens in a major histocompatibility complex (MHC)-dependent manner, CARs can potentially redirect the effector functions of a T cell toward any protein or non-protein target expressed on the cell surface. (frontiersin.org)
  • Similar to T-cell receptors (TCRs), functional genes of immunoglobulins (Igs) are the result of somatic recombination of DNA containing the relatively limited germinal genetic information, using the so-called V(D)J recombination process that occurs between individual genes (also referred to as gene segments) of the variable domains of the H and L chains (or α, β, γ, and δ chains of TCRs). (intechopen.com)
  • Regarding shared (self) tumor antigens, it is unclear whether the human CD4+ T cell repertoire has been shaped by tolerance mechanisms and lacks highly functional TCRs suitable for therapy. (jci.org)
  • Here, TCRs against the tumor-associated antigen NY-ESO-1 were isolated either from human CD4+ T cells or from mice that express a diverse human TCR repertoire with HLA-DRA/DRB1*0401 restriction and are NY-ESO-1 negative. (jci.org)
  • These data suggest that MHC II-restricted TCRs against NY-ESO-1 from a nontolerant nonhuman host are of optimal affinity and that the combined use of MHC I- and II-restricted TCRs against NY-ESO-1 can make adoptive T cell therapy more effective. (jci.org)
  • The general goal of this study was to determine the diversity of TCRs from specific T cell populations, including T cells that are reactive with multiple ligands and TCRs that are reactive with a single peptide/MHC protein complex. (illinois.edu)
  • This high variability is mediated by cell clone-specific, adaptive receptors on B and T cells, called B cell receptors (BCRs) and T cell receptors (TCRs). (springermedizin.de)
  • Engagement of antigen-specific T cell receptors (TCRs) is a prerequisite for T cell activation. (axonmedchem.com)
  • Activation of T cells occurs upon ligation of clonotypic T cell receptors (TCRs) by MHC molecules on antigen-presenting cells (APCs) presenting peptides (peptide-MHC) from either endogenously encoded self molecules or exogenously encoded pathogen molecules. (axonmedchem.com)
  • By engineering T cells to express the TCRs researchers can endow any CD4+ cell with the capability to directly recognize tumor antigen-expressing cancer cells, without requiring presentation of the antigen by an antigen presenting cell. (roswellpark.org)
  • T cell receptor (TCR) gene transfer employing high affinity TCRs recognizing defined tumor-associated antigens can potentially circumvent these challenges. (washington.edu)
  • The binding between TCR and antigen peptides is of relatively low affinity and is degenerate: that is, many TCRs recognize the same antigen peptide and many antigen peptides are recognized by the same TCR. (wikipedia.org)
  • Thinking that they could try to train the transplanted immune cells to attack cancer cells, scientists transferred lymphocytes into a rat with carcinogen-induced sarcoma. (biolegend.com)
  • T cell receptors are protein complexes found on the surface of a type of white blood cell called T lymphocytes (or T cells), part of the body's immune system. (sciencephoto.com)
  • molecules on the surface of t-lymphocytes that recognise and combine with antigens . (biology-online.org)
  • In contrast, antigen receptors on B and T lymphocytes diversify enormously in each individual: genes for these receptors composed of multiple various parts are assembled randomly through gene recombination during development of these cells throughout the life of the individuals. (springer.com)
  • Recent reports on severe adverse events associated with treatment of cancer patients with CAR- or T-cell receptor (TCR)-engineered T lymphocytes further illustrate the critical importance of target selection for safe and efficient therapy ( 4-7 ). (aacrjournals.org)
  • The results show that a subpopulation of mature tumor-associated myeloid cells express high levels of arginase I, whereas tumor cells and infiltrating lymphocytes do not. (aacrjournals.org)
  • More recently, in vitro models suggest that stimulation of T cells in an l -Arginine ( l -Arg) poor microenvironment results in the induction of signal transduction and functional alterations (10) similar to those seen in tumor-infiltrating lymphocytes and peripheral blood T cells of patients with cancer. (aacrjournals.org)
  • The earliest application of T cells was in the allotransplant setting where donor lymphocytes were used for the treatment of relapsed leukaemias. (lymphomacoalition.org)
  • Signals propagated through the B cell antigen receptor (BCR) are vital for the development and survival of B lymphocytes in both the bone marrow and the periphery. (semanticscholar.org)
  • The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. (wikipedia.org)
  • These cells could directly recognize tumor cells by genetic modification to express a chimeric antigen receptor (CAR), and they were activated to exhibit a durable persistence in vivo through the T-cell activation endodomain with costimulatory signaling molecules [ 1 , 2 ]. (hindawi.com)
  • The TCR has to be efficiently expressed, their affinity to the desired antigen should be high enough to recognize low amounts of endogenously processed peptides on tumor cells, and the TCR should not be cross-reactive to other antigens. (mdc-berlin.de)
  • Although one TCR most efficiently bound MHC-multimers loaded with NY-ESO-1 peptide, T cells expressing this transgenic TCR were not able to recognize endogenously processed antigen. (mdc-berlin.de)
  • Merck, a leading science and technology company, today announced that it has evolved its agreement with Intrexon Corporation (NASDAQ: XON) for the development of Chimeric Antigen Receptor T-cell (CAR-T) therapies, genetically engineered T-cells with synthetic receptors that recognize a specific antigen expressed on tumor cells. (presseportal.ch)
  • CAR-T cells utilize designer fusion proteins to recognize and specifically destroy cells bearing a target surface epitope. (urotoday.com)
  • First-generation CARs depended heavily upon a single-chain fragment variable to recognize tumor-associated antigens specifically, however, they lacked the costimulatory intracellular molecule (e.g. (urotoday.com)
  • Receptors on innate immune cells that recognize pathogens, such as Toll-like receptors, have been diversified and selected through evolution. (springer.com)
  • Genetic engineering of immune cells called T cells, allows the T cells to recognize and kill tumor cells that have the specific protein on their cell surface. (ca.gov)
  • T cells charge into action when they recognize foreign substances, or antigens, on cells. (berkeleywellness.com)
  • T cells recognize foreign antigen through a heterodimeric $\alpha\beta$ T-cell receptor (TCR). (illinois.edu)
  • These T cells recognize foreign MHC proteins and because MHC proteins can each bind a variety of endogenous peptides, the T cells recognize multiple ligands (i.e., different peptide/MHC complexes). (illinois.edu)
  • The T cells are genetically modified to better recognize and attack cancer. (medworm.com)
  • CD4+ T cells recognize peptide fragments presented on MHC class II (HLA class II in humans). (roswellpark.org)
  • Autologous transplantation followed by treatment with CTL019 cells led to a complete response with no evidence of progression and no measurable serum or urine monoclonal protein at the most recent evaluation, 12 months after treatment. (nih.gov)
  • We characterized three NY-ESO-1 antigen-reactive cytotoxic T lymphocyte (CTL) clones which were generated by different approaches of T cell priming (autologous, allogeneic), and transferred their TCR into donor T cells for more extensive evaluations. (mdc-berlin.de)
  • CAR-T cells can be either derived from T cells in a patient's own blood (autologous) or derived from the T cells of another healthy donor (allogeneic). (wikipedia.org)
  • CAR-T cells may be manufactured either from the patient's own blood, known as an autologous treatment, or from the blood of a healthy donor, known as an allogeneic treatment. (wikipedia.org)
  • Not surprisingly, this first wave of trials will include many hematological malignancy trials, and that should include those with autologous cellular immunotherapies, such as CAR-T cells. (urotoday.com)
  • Generally, leukapheresis is utilized to collect peripheral blood mononuclear cells to create autologous therapy. (urotoday.com)
  • The purpose of this study is to test the safety of delivering the patients' own immune cells, called T cells, after the high-dose chemotherapy (HDT) and autologous stem cell transplantation (ASCT). (clinicaltrials.gov)
  • JNJ-68284528 is an autologous chimeric antigen receptor T-cell (CAR-T) therapy that targets B-cell maturation antigen (BCMA). (centerwatch.com)
  • We investigated whether 2B4-enhanced activation signals can redirect the cytolytic function of human NK cells to NK cell-resistant and autologous leukemia and tumor targets. (aacrjournals.org)
  • Due to the high selectivity of the gene-modified NK cells for their tumor targets, NK cells from fully matched donors as well as autologous NK cells can be used. (aacrjournals.org)
  • Many malignant cells express MHC class I antigens and are thus naturally resistant to lysis by autologous NK cells. (aacrjournals.org)
  • Accordingly, the first clinical trials using adoptive transfer of autologous NK cells have failed to produce significant therapeutic effects ( 2 , 3 ). (aacrjournals.org)
  • Increasing awareness of the role of activating receptors in the recruitment of NK effector functions has motivated new efforts to target autologous malignancies. (aacrjournals.org)
  • Indeed, engagement of activating NK cell receptors by ligands expressed on tumor cells can overcome inhibitory signals and stimulate NK cell responses even in the presence of autologous MHC class I ( 6 , 7 ). (aacrjournals.org)
  • Although high dose chemotherapy, followed by autologous stem cell transplantation remains the standard of care at relapse, this treatment modality leads to a cure in less than 50% of the patients. (medworm.com)
  • High-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT) is the standard of care for relapsed or primary refractory (rel/ref) chemorefractory diffuse large B-cell lymphoma. (medworm.com)
  • The clinic offers integrated medical treatments like bio-cellular medicine treatments, adult autologous stem cell, general medical care, immunomodulating bio-enzyme systems, advanced ultrasonic diagnostic imaging, basic diagnostic tests, integrative medicine services, non-invasive regenerative procedures, nutrition counseling along with customized plans and wellness services to the patients. (placidway.com)
  • Accordingly, we developed a rhesus macaque (RM) model of neurotoxicity via adoptive transfer of autologous CD20-specific CAR T cells. (aacrjournals.org)
  • The peptide V beta 3-(57-77) also inhibited SEA-induced interferon-gamma production and SEA-induced proliferation of B10.BR spleen cells. (pnas.org)
  • The peptide inhibition of SEA-induced function was due at least in part to inhibition of V beta 3-bearing T-cell activity, since the percentage of T cells reactive with an anti-V beta 3 monoclonal antibody was significantly reduced by V beta 3-(57-77). (pnas.org)
  • A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens. (sigmaaldrich.com)
  • Here, we have described Pr20, a TCR mimic (TCRm) human IgG1 antibody that recognizes the cell-surface ALY peptide/HLA-A2 complex. (sigmaaldrich.com)
  • The data provide rationale for developing TCRm antibodies as therapeutic agents for cancer, offer mechanistic insight on proteasomal regulation of tumor-associated peptide/HLA antigen complexes, and yield possible therapeutic solutions to target antigens with ultra-low surface presentation. (sigmaaldrich.com)
  • This complex participates in T-cell activation upon the presentation of the antigen peptide (derived from the foreign antigen) bound to the MHC (Class I and Class II) residing on antigen-presenting cells (APCs), including dendritic cells, macrophages and B cells. (wikipathways.org)
  • These findings are also discussed with regard to the potential for targeting autoimmune T cells and for peptide-based therapies that involve T-cell mediated tumor rejection. (illinois.edu)
  • Mice immunized with this peptide generate a diverse T cell response, recruiting T cells of multiple TCR Vbeta families and encompassing an avidity range of three logs. (washington.edu)
  • When the TCR engages with antigenic peptide and MHC (peptide/MHC), the T lymphocyte is activated through signal transduction, that is, a series of biochemical events mediated by associated enzymes, co-receptors, specialized adaptor molecules, and activated or released transcription factors. (wikipedia.org)
  • The Constant region is proximal to the cell membrane, followed by a transmembrane region and a short cytoplasmic tail, while the Variable region binds to the peptide/MHC complex. (wikipedia.org)
  • CDR3 is the main CDR responsible for recognizing processed antigen, although CDR1 of the alpha chain has also been shown to interact with the N-terminal part of the antigenic peptide, whereas CDR1 of the β-chain interacts with the C-terminal part of the peptide. (wikipedia.org)
  • Because cancer cells are produced by the body internally, they may not carry a foreign antigen on their surface, so T cells have trouble spotting them. (berkeleywellness.com)
  • Investigators optimized the design of CARs to enhance receptor mediated T cell signaling and demonstrated that second and third generation CARs, including various costimulatory molecules, resulted in enhanced T-cell persistence and sustained antitumor activity in both in vitro and in vivo mouse models as well as clinical trials. (nih.gov)
  • Therefore, target cell surface molecules can be found on the surface of NK cells. (plos.org)
  • This technique seems generalizable to biochemical and structural studies of many other cell surface molecules as well. (sciencemag.org)
  • Antigens (foreign proteins) are presented to T cell receptors by MHC molecules to effect an immune response. (sciencephoto.com)
  • left and middle) Individual BCR molecules in TIRF images from one typical μ-High or μ-Low J558L cell ( Video 1 ) indicating the instant diffusion coefficient (D 0 ) by pseudocolored spots. (rupress.org)
  • C-H) The D 0 values for all BCR molecules from μ-High and μ-Low J558L cells (C-E) or B1-8 primary B cells (F-H) labeled with Alexa Fluor 568-Fab anti-IgM placed on planar lipid bilayers containing no antigen, NIP1-His12, or pNP1-His12. (rupress.org)
  • 1 These costimulatory molecules successfully promote the production of cytokines such as IL-2 that activate, proliferate, and prolong survival of T cells. (urotoday.com)
  • While T-cell antigen receptor (TCR) recognizes antigenic peptides of proteins presented on the self MHC, B-cell antigen receptor (BCR) recognizes essentially any kinds of molecules. (springer.com)
  • Preclinical studies showed that inclusion of potent signaling molecules improves the antitumor activity of genetically modified T cells. (jcancer.org)
  • Subsequently, it was further documented that RP215 not only reacts with the epitope of immunoglobulin heavy chains, but also many other immunoglobulin superfamily (IgSF) proteins including antigen receptors, such as immunoglobulins and T-cell receptors, as well as cell adhesion molecules [ 3 , 4 ]. (omicsonline.org)
  • Tumor Necrosis Factor Receptor Superfamily Member 9 (4-1BB Ligand Receptor or T Cell Antigen 4-1BB Homolog or T Cell Antigen ILA or CD137 or TNFRSF9) pipeline Target constitutes close to 28 molecules. (researchandmarkets.com)
  • Several myeloma target antigens are being investigated in clinical trials of patients with R/R multiple myeloma, including B-cell maturation antigen (BCMA), CD38, CD138, SLAMF7, and natural killer group 2D. (medscape.com)
  • This article gives an overview on the state-of-the art of preclinical and clinical studies on suitable target antigens for CAR T cell therapy in AML patients. (mdpi.com)
  • Hematological malignancies tend to be more homogenous with a uniform expression of target antigens which may explain the high response rates and durability after CAR-T cell therapy. (urotoday.com)
  • Kimoto, Y. (1998) Expression of heavy-chain constant region of immunoglobulin and T-cell receptor gene transcripts in human non-hematopoietic tumor cell lines. (scirp.org)
  • Our data indicate that multiple parameters of TCR gene-modified T cells have to be evaluated to identify an optimal TCR candidate for adoptive therapy. (mdc-berlin.de)
  • Brummer T, Shaw PE, Reth M, Misawa Y (2002) Inducible gene deletion reveals different roles for B-Raf and Raf-1 in B-cell antigen receptor signalling. (springer.com)
  • Protein tyrosine phosphorylation subsequently leads to the activation of multiple pathways, including ERK (Extracellular Signal Regulated Kinase), JNK (c-Jun N-terminal Kinase), NF-κB (Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1) and NFAT(Nuclear Factor of Activated T-Cells) pathways, which ultimately induce effector functions. (wikipathways.org)
  • ZAP70 also activates IKKs via the CARD11 (Caspase recruitment domain family, member 11) -BCL10 (B-Cell CLL/lymphoma-10)-MALT1 (Mucosa Associated Lymphoid Tissue Lymphoma Translocation Gene-1) complex and MAP3K (activated by PKCθ) which in turn relieve NF-κB of IκB (NF-kappa-B inhibitor beta) and allow its nuclear translocation and transcriptional activation. (wikipathways.org)
  • In addition, the safety of giving these gene modified cells to humans will be tested at different cell doses. (centerwatch.com)
  • Additional objectives are to determine if this therapy can cause regression of B cell cancers and to measure if the gene modified cells survive in patients blood. (centerwatch.com)
  • The success of adoptive T cell gene transfer for treatment of cancer and HIV is predicated on generating a response that is both durable and safe. (sciencemag.org)
  • These findings indicate that host immunosuppression before T cell transfer is not required to achieve long-term persistence of gene-modified T cells. (sciencemag.org)
  • Until recently, development of this technology has been limited by lack of efficient T cell culture systems and gene transfer techniques. (jcancer.org)
  • The MCL BCR seems to be antigen-experienced since it shows biased immunoglobulin heavy variable (IGHV) gene usage and suggestive patterns of clonal diversification despite low levels of somatic hypermutation. (haematologica.org)
  • Genetic profiling studies suggest that the normal counterpart of PCNSL cells are late germinal center (GC) exit B-cells with a gene expression profile characteristic of both GC B-cells and activated B-cells (ABC) ( 1 , 4 ). (frontiersin.org)
  • Then the lab [performs] a gene transfer, to teach the T cells to target a protein found on the surface of B cells , another type of blood cell that's affected in leukemia. (fightaging.org)
  • In this article, we describe a gene engineering strategy that efficiently modulates the balance of human NK cell signals toward tumor-specific activation. (aacrjournals.org)
  • Selecting highly tissue-restricted antigens, cancer testis antigens, mutated gene products or viral proteins as targets could significantly improve the safety profile of using CART cells. (aacrjournals.org)
  • To characterize these T cells at the molecular level, we compared the T cell antigen receptor (TcR) variable (V) region gene usage in thyroid, retroorbital, pretibial tissue, and peripheral blood mononuclear cells of two patients with Graves' disease, ophthalmopathy, and pretibial dermopathy. (uni-muenchen.de)
  • Since RP215 was shown to induce apoptosis and inhibit tumor growth in nude mouse models, the effects of RP215 and antibodies against antigen receptors on the gene regulations of cultured OC-3-VGH ovarian and C-33A cervical cancer cells were investigated through semi-quantitative RT-PCR. (omicsonline.org)
  • Among toll-like receptor genes (TLR-2, -3, -4, -6, -7 and -9), differential levels of gene expressions in different cancer cell lines were observed. (omicsonline.org)
  • Integration of B-cell receptor-induced ERK1/2 phosphorylation and mutations of SF3B1 gene refines prognosis in treatment-naïve chronic lymphocytic leukemia. (semanticscholar.org)
  • This invention describes sequences of TCR α and β chain genes from a novel tumor-recognizing CD4+ T cell clone as well as a method to prepare a large number of tumor recognizing CD4+ T cells by TCR gene transfer. (roswellpark.org)
  • Provision of "CD4 help" by current gene-engineered CD4+ T cells is expected to enhance the anti-tumor immune responses and overcome immunosuppression at the local tumor sites. (roswellpark.org)
  • Adoptive T-cell therapy of B-cell malignancies: conventional and physiological chimeric antigen receptors. (nih.gov)
  • We highlight advances in the use of CARs in the treatment of B-cell malignancies and future challenges in the use of adoptive therapy with CAR-engineered T cells. (nih.gov)
  • Recent studies have highlighted the successes of chimeric antigen receptor-modified T- (CART-) cell-based therapy for B-cell malignancies, and early phase clinical trials have been launched in recent years. (hindawi.com)
  • After two decades of preclinical research and clinical trials, the safety and feasibility of CART-cell-based therapy have been confirmed, and unprecedented clinical results have been obtained in hematological malignancies [ 3 - 5 ]. (hindawi.com)
  • These clinical studies indicate that CART-cell therapy can produce clinical responses in patients with advanced hematological malignancies. (hindawi.com)
  • Current status of clinical trials of chimeric antigen receptor-modified T (CART) cells in malignancies. (hindawi.com)
  • Maus MV, Grupp SA, Porter DL, June CH. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. (springer.com)
  • In several human malignancies, the expression of receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is associated with aggressive characteristics and poor overall survival. (hindawi.com)
  • Porter DL, Kalos M, Zheng Z, Levine B, June C. Chimeric Antigen Receptor Therapy for B-cell Malignancies. (jcancer.org)
  • Expression is restricted to B cells, from the pro-B cell stage to mature B cells (though not on plasma cells), possibly follicular dendritic cells, and it is expressed on the surface of most B cell malignancies. (jcancer.org)
  • Given these preliminary findings, we have initiated a clinical trial to test the feasibility and safety of CART-19 cells in patients with CD19+ lymphoid malignancies. (jcancer.org)
  • This resulted in the development of targeted inhibitors for the treatment of several B-cell malignancies, especially chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). (haematologica.org)
  • Our data thus pave the way toward the clinical application of NK cells for the efficient and specific elimination of minimal residual tumor cells in various malignancies. (aacrjournals.org)
  • Several novel T cell-engaging therapies - including chimeric antigen receptor-modified T-cells (CART) and blinatumomab, a novel bispecific T-cell engaging (BiTE) single-chain antibody - have shown promise in the treatment refractory pediatric malignancies. (chop.edu)
  • However, patients with inherent- or acquiredresistance to first-line treatment options exhibit poor prognosis signifying the need for development of an optimal treatment approach for relapsed/ refractory malignancies of B cell origin. (pulsus.com)
  • Treating hematologic malignancies with chimeric antigen receptor T cells / James N. Kochenderfer. (nih.gov)
  • The vector encoded a chimeric antigen receptor (CAR) composed of CD4 linked to the CD3ζ signaling chain (CD4ζ). (sciencemag.org)
  • Antigen receptors, including immunoglobulins and T-cell receptors, are known to be widely expressed by cancer cells through unconfirmed mechanisms and for unknown purposes. (scirp.org)
  • RP215 is a monoclonal antibody generated against a carbohydrate-associated epitope of glycoproteins designated as CA215, which consists mainly of immunoglobulin superfamily proteins expressed by cancer cells including antigen receptors such as immunoglobulins and T-cell receptors. (omicsonline.org)
  • Chimeric antigen receptors (CARs) are synthetic proteins expressed on the surface of T cells. (medscape.com)
  • Here we have studied the dynamic activity of proteins involved in regulating actin polymerization in live T cells after activation. (nature.com)
  • Two such adaptor proteins, Nck and the Wiskott-Aldrich syndrome protein (WASp), were recruited to the TCR during initial T cell activation, where they colocalized with the tyrosine kinase Zap70. (nature.com)
  • Samelson, L.E. Signal transduction mediated by the T cell antigen receptor: the role of adaptor proteins. (nature.com)
  • Chimeric antigen receptors (CARs, also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors) are receptor proteins that have been engineered to give T cells the new ability to target a specific protein. (wikipedia.org)
  • This work prompted CD3ζ intracellular domains to be added to chimeric receptors with antibody-like extracellular domains, commonly single-chain fraction variable (scFV) domains, as well as proteins such as CD4, subsequently termed first generation CARs. (wikipedia.org)
  • Chimeric antigen receptors (CARs) are special receptors that are designed to bind to certain proteins on cancer cells. (ca.gov)
  • All the above components along with accessory proteins essential for MHC are a part of the immunological synapse that initiates T-cell activation. (wikipathways.org)
  • CD45 plays a role in antagonizing the effect of inhibitory proteins on T-cell activation. (wikipathways.org)
  • To generate T cells involved in transplant rejection, mice were injected at least two times (hyperimmunized) with cells that bear foreign MHC proteins and the "transplant-reactive" T cells were further enriched in culture. (illinois.edu)
  • 2004) Expression of immunoglobulin kappa light chain constant region in abnormal human cervical epithelial cells. (scirp.org)
  • Chen, Z. and Gu, J. (2007) Immunoglobulin G expression in carcinomas and cancer cell lines. (scirp.org)
  • 2007) Immunoglobulin alpha heavy chain derived from human epithelial cancer cells promotes the access of S phase and growth of cancer cells. (scirp.org)
  • 2007) Expression and secretion of immunoglobulin alpha heavy chain with diverse VDJ recombinations by human epithelial cancer cells. (scirp.org)
  • Statistical comparison of all inhibitory and activating killer cell immunoglobulin receptors (KIRs) between controls, survivors, and persons who died of Ebola virus disease in Guinea, 2015-2017. (cdc.gov)
  • Results from this study showed that: (1) unlike immunoglobulin genes, somatic mutations did not occur in TCR genes from "hyperimmune" animals and (2) TCR transcripts from "hyperimmune" T cells specific for foreign MHC were diverse in sequence. (illinois.edu)
  • In accordance with this, PCNSLs show rearranged immunoglobulin genes, ongoing somatic hypermutation, and persistent B cell lymphoma 6 (BCL6) activity but lack terminal B-cell differentiation resulting in a fixed IgM/IgD phenotype ( 5 - 8 ). (frontiersin.org)
  • Inhibitory receptors [e.g., killer immunoglobulin receptors (KIR)] interact with self-MHC class I antigens and protect normal cells from NK cell attack. (aacrjournals.org)
  • In this way the MHC-TCR-CD3 interaction for T cells is functionally similar to the antigen(Ag)-immunoglobulin(Ig)-FcR interaction for myeloid leukocytes, and Ag-Ig-CD79 interaction for B cells. (wikipedia.org)
  • The intracellular domains ensure intracellular signaling necessary to activate the effector functions of the CAR T cell. (medscape.com)
  • The successful use of chimeric antigen receptors (CARs) for the generation of antigen-specific effector T cells suggests that a similar approach could be used to generate alloantigen-specific Tregs. (jci.org)
  • Combinational targeting offsets antigen escape and enhances effector functions of adoptively transferred T cells in glioblastoma. (springer.com)
  • CARs are engineered receptors, stably or transiently transduced into T cells, that aim to enhance T cell effector function by recognizing and binding to a specific tumor-associated antigen. (mdpi.com)
  • Chimeric antigen receptors (CARs) significantly enhance the anti-tumor activity of immune effector cells. (ca.gov)
  • Safety evaluations will include a review of adverse events, laboratory test results, vital sign measurements, physical examination findings (including neurologic examination), assessment of cardiac function, immune effector cell-associated encephalopathy (ICE) score, handwriting assessment, and assessment of Eastern Cooperative Oncology Group (ECOG) performance status grade. (centerwatch.com)
  • More importantly, EGFRvIII-CART specifically and efficiently recognized and killed A549-EGFRvIII cells with an effector/target ratio of 10:1 by expressing and releasing cytokines, including perforin, granzyme B, IFN-g, and TNF-α. (springer.com)
  • Acquisition of appropriate effector T cell function requires the participation of multiple signals from the T cell microenvironment. (axonmedchem.com)
  • Optimization of design, improving tumor microenvironment and combinations with other therapies may help us in improving CAR T cell efficacy. (springer.com)
  • In 2017, the Food and Drug Administration (FDA) approved tisagenlecleucel (Kymriah®) and axicabtagene ciloleucel (Yescarta®) CAR T-cell therapies for the treatment of certain relapsed or refractory leukemias and lymphomas. (cms.gov)
  • The first CAR-T cell therapies were FDA-approved in 2017, and there are now 5 approved CAR-T therapies. (wikipedia.org)
  • The reason this treatment option is appealing is that it is ready for immediate use, compared with other CAR therapies that require the use of a patient's own genetically modified T cells, which are then created through a multi-week manufacturing process, according to a press release issues by The University of Texas MD Anderson Cancer Center (MD Anderson). (curetoday.com)
  • Yet as a genitourinary oncologist, I have a mild sense of envy on this topic of CAR-T cell therapy, as I hope for a day where our patients can be treated with these exciting therapies. (urotoday.com)
  • Isolation and genetic modification of T cells for current CAR-T therapies are done on a patient-specific basis, which is time-consuming and expensive. (ca.gov)
  • As with all aggressive cancer therapies, CAR T-cell therapy has serious drawbacks. (berkeleywellness.com)
  • Autoimmune diseases such as lupus and rheumatoid arthritis lack therapies that specifically target only the disease-causing cells. (sciencemag.org)
  • A smooth translation from lab bench to clinical-grade GMP manufacturing is of particular importance for the development of successful CAR T cell therapies. (miltenyibiotec.com)
  • Therefore, arginase I production by mature myeloid cells in the tumor microenvironment may be a central mechanism for tumor evasion and may represent a target for new therapies. (aacrjournals.org)
  • Stem cell therapies have big potential and its usefulness for treating lung diseases can also have great appeal. (placidway.com)
  • Adoptive transfer of T cells engineered to express a chimeric antigen receptor (CAR) is an effective therapy for select lymphomas. (sciencemag.org)
  • When these cells were engineered to express a chimeric costimulatory receptor, they specifically recognized transformed, but not healthy, myeloid cell targets. (sciencemag.org)
  • We engineered human T cells to express a chimeric autoantibody receptor (CAAR), consisting of the PV autoantigen, desmoglein (Dsg) 3, fused to CD137-CD3ζ signaling domains. (sciencemag.org)
  • Together, our results demonstrate that use of CAR technology to generate potent, functional, and stable alloantigen-specific human Tregs markedly enhances their therapeutic potential in transplantation and sets the stage for using this approach for making antigen-specific Tregs for therapy of multiple diseases. (jci.org)
  • Targeting pathways that limit antigen-induced mast cell activation may have greater therapeutic efficacy by inhibiting the synthesis and release of many proinflammatory mediators produced in the mast cell. (aspetjournals.org)
  • The B-Cell Lymphoma Moon Shot is revolutionizing the conventional medical research approach to rapidly translate findings into patient treatment options and develop personalized therapeutic strategies. (mdanderson.org)
  • SLP-76 Coordinates Nck-dependent Wiskott-Aldrich syndrome protein recruitment with Vav-1/cdc42-dependent Wiskott-Aldrich syndrome protein activation at the T cell-APC contact Site. (nature.com)
  • 2001) Proteomic detection of changes in protein synthesis induced by NGX6 transfected in human nasopharyngeal carcinoma cells. (scirp.org)
  • ZAP70 induces activation of LAT (Linker for Activation of T-Cells), an integral membrane adaptor protein which further binds to GADS (Growth Factor Receptor-Bound Protein-2-Related Adaptor Protein-2), SLP76 (SH2 Domain-Containing Leukocyte Protein-76), and ITK (IL-2 inducible T-cell kinase). (wikipathways.org)
  • Engineered T cells are a promising form of synthetic biology for long-term delivery of protein-based therapeutics. (sciencemag.org)
  • The T cells are then transplanted back into the patient, where they hunt and kill anything with the protein attached to it. (fightaging.org)
  • Rituximab binds to CD20, a protein found on B cells, resulting in the killing of cancer cells. (lymphomacoalition.org)
  • In contrast, other part of the same antigen-specific CD4+ T cells, "non-tumor-recognizing CD4+ T cells (NTR-CD4)", only recognizes the exogenous tumor antigen protein after processing by antigen-presenting cells. (roswellpark.org)
  • these methods include protein production, X-ray crystallography, biophysics, and functional T-cell experiments. (jove.com)
  • Our results suggest that a cell surface protein(s) of 85 to 90 kDa is, or constitutes a portion of, a specific receptor for the PA. (asm.org)
  • CAR T cells are genetically engineered T cells with major histocompatibility complex-independent, tumor-specific, immune-mediated cytolytic actions against cancer cells. (springer.com)
  • T cells genetically engineered with chimeric antigen receptor (CAR) vectors can specifically target the surface antigen of cancer cells and kill them in an MHC-independent manner. (eurekaselect.com)
  • What is the efficacy of chimeric antigen receptor (CAR) T-cell therapy for multiple myeloma? (medscape.com)
  • Celgene Corporation and bluebird bio has been granted Breakthrough Therapy Designation from FDA and Prime Eligibility from EMA for bb2121 Anti-BCMA CAR-T Cell Therapy for Relapsed and Refractory Multiple Myeloma. (marketresearch.com)
  • How these abundant receptors remain silent on resting B cells and how they can be activated by a molecularly diverse set of ligands is poorly understood. (nih.gov)
  • Similarly, T cells captured NKG2D and NKp46 ligands on tumor cells through trogocytosis and promoted NK cell activity [12] . (plos.org)
  • Current methods to generate alloantigen-specific Tregs rely on expansion with allogeneic antigen-presenting cells, which requires access to donor and recipient cells and multiple MHC mismatches. (jci.org)
  • Curing Ph+ ALL: assessing the relative contributions of chemotherapy, TKIs, and allogeneic stem cell transplant. (medworm.com)
  • Hitherto, allogeneic hemotopoietic stem cell transplantation (allo-HSCT) is the best curative treatment option in intermediate and high risk AML. (mdpi.com)
  • This is the basis for the graft-versus-leukemia (GVL) effect, which contributes in part to the efficacy of allogeneic stem cell transplantation (SCT) and is the rationale for donor lymphocyte infusion in leukemia. (bloodjournal.org)
  • We are encouraged by the results of the clinical trial, which will launch further clinical studies to investigate allogeneic cord blood-derived CAR NK cells as a potential treatment option for patients in need," corresponding author Dr. Katy Rezvani, professor of stem cell transplantation and cellular therapy at MD Anderson, said in a press release. (curetoday.com)
  • 50%, despite allogeneic stem cell transplant following second remission. (centerwatch.com)
  • This strategy promises to extend the use of NK cells in cancer therapy beyond allogeneic mismatched hematopoietic stem cell transplantation. (aacrjournals.org)
  • Structures of many of the cell surface receptor-ligand complexes mediating the interactions between T cells and target cells have been determined in the past ten years. (nih.gov)
  • Chang CC, Campoli M, Ferrone S. Classical and nonclassical HLA class I antigen and NK Cell-activating ligand changes in malignant cells: current challenges and future directions. (springer.com)
  • The CAR consists of an antibody or ligand-derived targeting ectodomain fused with a hinge, a trans-membrane domain, and intracellular T cell signaling domains. (frontiersin.org)
  • The interaction of the T cell receptor for antigen (TCR) with its antigen-major histocompatibility complex ligand is difficult to study because both are cell surface multimers. (sciencemag.org)
  • AICD in T cells has been suggested to be mediated mainly by Fas (CD95)/Fas-ligand (Fas-L) interaction ( 6 ), and also has been modulated by environmental constituents ( 7 , 8 ). (jimmunol.org)
  • The T-cell antigen receptor (TCR) complex is composed of a ligand-binding subunit, the α and β chains, and a signaling subunit, namely the CD3ε, γ and δ chains and the TCRζ chain. (wikipathways.org)
  • Interestingly, these signals are known to be either ligand-independent ('tonic' signals) or induced by ligand (antigen) binding to the BCR. (semanticscholar.org)
  • Additionally, an incidental match between male HLA-C2 and female HLA-C1 ligand KIR receptors might perturb the balance between activatory and inhibitory KIR-ligand interactions during pregnancy in couples affected by RPL. (physiciansweekly.com)
  • Tumor Necrosis Factor Receptor Superfamily Member 9 (4-1BB Ligand Receptor or T Cell Antigen 4-1BB Homolog or T Cell Antigen ILA or CD137 or TNFRSF9) - Tumor necrosis factor receptor superfamily member 9 (TNFRSF9), also known as CD137 is a member of the tumor necrosis factor (TNF) receptor family. (researchandmarkets.com)
  • The latest report Tumor Necrosis Factor Receptor Superfamily Member 9 - Pipeline Review, H1 2018, outlays comprehensive information on the Tumor Necrosis Factor Receptor Superfamily Member 9 (4-1BB Ligand Receptor or T Cell Antigen 4-1BB Homolog or T Cell Antigen ILA or CD137 or TNFRSF9) targeted therapeutics, complete with analysis by indications, stage of development, mechanism of action (MoA), route of administration (RoA) and molecule type. (researchandmarkets.com)
  • It also reviews key players involved in Tumor Necrosis Factor Receptor Superfamily Member 9 (4-1BB Ligand Receptor or T Cell Antigen 4-1BB Homolog or T Cell Antigen ILA or CD137 or TNFRSF9) targeted therapeutics development with respective active and dormant or discontinued projects. (researchandmarkets.com)
  • We'll be discussing immune checkpoint blockade (and one of our new product lines, GoInVivo ™) in another blog, however this post will focus on another type of immune therapy, called adoptive cell transfer, also known as ACT. (biolegend.com)
  • We have examined the interaction of the microbial superantigen staphylococcal enterotoxin A (SEA) with peptides corresponding to overlapping regions of the T-cell antigen receptor beta chain variable region V beta 3. (pnas.org)
  • These data indicate that the 2B4 receptor has a potent costimulatory effect in NK cells. (aacrjournals.org)
  • Initial studies of CAR T cell therapy have shown promising results in ovarian cancer, but there are some obstacles like impaired T cell trafficking, lack of antigenic targets, cytokine release syndrome and most important immunosuppressive tumor microenvironment. (springer.com)
  • The majority of patients who received CAR T-cell therapy also experienced adverse events including cytokine release syndrome and neurologic effects. (cms.gov)
  • Supraphysiologic T-cell proliferation, a hallmark of this therapy, contributes to both efficacy and the most notable toxicity, cytokine release syndrome (CRS), posing a unique challenge for toxicity management. (bloodjournal.org)
  • Mast cell activation results in the immediate release of proinflammatory mediators prestored in cytoplasmic granules, as well as initiation of lipid mediator production and cytokine synthesis by these resident tissue leukocytes. (aspetjournals.org)
  • Here, using a panel of mice lacking various combinations of adenosine receptors, and mast cells derived from these animals, we show that adenosine receptor agonists provide an effective means of inhibition of mast cell degranulation and induction of cytokine production both in vitro and in vivo. (aspetjournals.org)
  • We identify A 2B as the primary receptor limiting mast cell degranulation, whereas the combined activity of A 2A and A 2B is required for the inhibition of cytokine synthesis. (aspetjournals.org)
  • Chen D, Heath V, O'Garra A, Johnston J, McMahon M (1999) Sustained activation of the raf-MEK-ERK pathway elicits cytokine unresponsiveness in T cells. (springer.com)
  • Grade 3+ cytokine release syndrome was associated with polyfunctional T cells, and both grade 3+ neurologic toxicity (NT) and antitumor efficacy were associated with polyfunctional IL-17A-producing T cells. (bloodjournal.org)
  • The proliferation of CAR-T cells were induced by cytokine and specific antigen in vitro . (springer.com)
  • Chimeric 2B4 signaling alone failed to induce interleukin-2 receptor up-regulation and cytokine secretion but triggered a specific degranulation response. (aacrjournals.org)
  • Clinical studies conducted by physician scientists at the CCCR have demonstrated that administration of tocilizumab - a recombinant humanized anti-IL6 receptor monoclonal antibody that interferes with secretion of the cytokine IL6 - can be an effective treatment for pediatric patients who develop CRS after CART or BiTE therapy. (chop.edu)
  • The first chimeric receptors containing portions of an antibody and the T cell receptor was described in 1987 by Yoshikazu Kuwana et al. (wikipedia.org)
  • In 1991, chimeric receptors containing the intracellular signaling domain of CD3ζ were shown to activate T cell signaling by Arthur Weiss at the University of California, San Francisco. (wikipedia.org)
  • They engineered T cells to express chimeric receptors consisting of the disease-causing autoantigen desmoglein 3 fused to signaling domains that activate T cells. (sciencemag.org)
  • This approach has been tested in vitro with CD30+ hematopoietic stem cells and CD30+ tumor cells and in vivo in mice transplanted with human CD30+ hematopoietic stem cells. (innovations-report.com)
  • In vivo experiments provided evidence that the treatment with anti-CD30 T-cells has no unwanted impact on the endogenous immune system. (innovations-report.com)
  • Additionally, CAR-NK cells demonstrate in vivo activity similar to that of CAR-T cells, but with less toxicity. (ca.gov)
  • Dsg3 CAAR-T cells exhibit specific cytotoxicity against cells expressing anti-Dsg3 BCRs in vitro and expand, persist, and specifically eliminate Dsg3-specific B cells in vivo. (sciencemag.org)
  • We presented data showing that the CART-19 cells expressing the 4-1BB signaling domain can have unprecedented and massive in-vivo expansion, traffic to tumor sites, persist long term in vivo, and induce rapid and potent anti-tumor activity in chemotherapy refractory CLL patients. (jcancer.org)
  • Therefore, most clinical applications have resulted in limited in vivo expansion and persistence of CAR-modified T cells resulting in disappointing clinical activity 3 , 4 . (jcancer.org)
  • By inclusion of the 4-1BB signaling domain, in vitro tumor cell killing, and in-vivo anti-tumor activity and persistence of CART-19 cells in a murine xenograft model of human ALL is greatly enhanced 7 . (jcancer.org)
  • 6 , 7 In addition, the BCR pathway is active in MCL cells in vitro and in vivo , and inhibiting the partially overexpressed key molecule Syk resulted in the induction of apoptosis in vitro . (haematologica.org)
  • The in vivo study indicated that the metastasis of A549-EGFRvIII cells in mice were inhibited by EGFRvIII-CART cells, and the survival of the mice was significantly prolonged with no serious side effects. (springer.com)
  • EGFRvIII-CART showed significantly efficient antitumor activity against lung cancer cells expressing EGFRvIII in vivo and in vitro . (springer.com)
  • Differential regulation of T-cell dependent and T-cell independent antibody responses through arginine methyltransferase PRMT1 in vivo. (semanticscholar.org)
  • We have discussed basic functioning of CAR T cells, their rationale and clinical outcome in ovarian cancer with limitations. (springer.com)
  • A phase I clinical trial of adoptive T cell therapy using IL-12 secreting MUC-16(ecto) directed chimeric antigen receptors for recurrent ovarian cancer. (springer.com)
  • Recent published clinical studies on CART cells specific for solid tumor antigens. (hindawi.com)
  • While success has been achieved in a number of studies, and two CAR-T-cell products were recently approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) (YESCARTA ® , KYMRIAH ® ), this treatment modality continues to present challenges for clinical development. (springer.com)
  • We anticipate these modifications will further expand CAR T cell therapy in clinical practice. (frontiersin.org)
  • Thus, the CAR is most suitable for clinical application in targeting CD30+ leukemia and lymphoma cells. (innovations-report.com)
  • A clinical study phase I is planned for early 2016, indication: cutaneous T-cell lymphoma. (innovations-report.com)
  • While most clinical approaches have focused on CD8+ T cells, the importance of CD4+ T cells in mediating tumor regression has become apparent. (jci.org)
  • In this review, we provide a summary of CAR T cell preclinical studies and clinical trials for malignant pleural mesothelioma (MPM), a rare, locally invasive pleural cancer with poor prognosis. (mdpi.com)
  • A first generation CAR containing a CD4 extracellular domain and a CD3ζ intracellular domain was used in the first clinical trail of chimeric antigen receptor T cells by the biotechnology company Cell Genesys in the mid 1990s, allowing adoptively transferred T cells to target HIV infected cells, although it failed to show any clinical improvement. (wikipedia.org)
  • The polyfunctionality strength index of manufactured CAR T cells were associated with clinical response and toxicities. (bloodjournal.org)
  • However, the association of preinfusion CAR product T-cell functionality with clinical outcomes has not been reported. (bloodjournal.org)
  • A prespecified T-cell polyfunctionality strength index (PSI) applied to preinfusion CAR product was significantly associated with clinical response, and PSI combined with CAR T cell-expansion or pretreatment serum IL-15 levels conferred additional significance. (bloodjournal.org)
  • Within the total product cell population, associations with clinical outcomes were greater with polyfunctional CD4+ T cells compared with CD8+ cells. (bloodjournal.org)
  • The findings in this exploratory study show that a preinfusion CAR product T-cell subset with a definable polyfunctional profile has a major association with clinical outcomes of CAR T-cell therapy. (bloodjournal.org)
  • In clinical trials, CAR T-cell therapy has emerged as an approach that can elicit long-lasting remission in hard-to-treat blood cancers. (berkeleywellness.com)
  • During early clinical trials, most patients developed an immune reaction to the infusion of CAR T cells. (berkeleywellness.com)
  • We report long-term results from three clinical trials to evaluate gammaretroviral vector-engineered T cells for HIV. (sciencemag.org)
  • Except for a few indolent cases, MCL typically has a rapid growth requiring immediate treatment, which places MCL in clinical proximity to other aggressive lymphomas such as diffuse large B cell lymphoma (DLBCL). (springermedizin.de)
  • Miltenyi Biotec offers product solutions for both CAR T cell research and clinical manufacturing needs. (miltenyibiotec.com)
  • A number of clinical trials have examined the use of CAR T-cell therapy. (lymphomacoalition.org)
  • To do this, they transfected a patient's own T cells with special T cell receptors that are engineered to be specific to a tumor antigen. (biolegend.com)
  • Doctors must use an individual patient's T cells so the immune system doesn't reject them. (berkeleywellness.com)
  • For this method, the researchers harvest a patient's T cells using a process like blood transfusion. (fightaging.org)
  • Chimeric antigen receptor T-cell, or CAR T-cell, therapy involves the laboratory reprogramming of a patient's T cells, which are a type of white blood cell responsible for protecting the body against infection and disease. (medworm.com)
  • City of Hope will re-engineer a patient's immune system central memory T cells (TCM cells) to express chimeric antigen receptors (CAR). (ca.gov)
  • Stem cell therapy for autism can enhance the blood and oxygen flow to the patient's brain by stimulating the formation of new arteries and by replacing the damaged neurons. (placidway.com)
  • White blood cells that include T cells are removed from the patient's body through a process called leukapheresis . (lymphomacoalition.org)
  • To our knowledge, this is the first report that describes the increased cytotoxicity of NK cells following the acquisition of CARs via trogocytosis. (plos.org)
  • RP215 and anti-antigen receptor antibodies were equally effective in inducing apoptosis and complement-dependent cytotoxicity reactions to cultured cancer cells. (scirp.org)
  • CAR-T cells destroy cells through several mechanisms, including extensive stimulated cell proliferation, increasing the degree to which they are toxic to other living cells (cytotoxicity) and by causing the increased secretion of factors that can affect other cells such as cytokines, interleukins and growth factors. (wikipedia.org)
  • An afucosylated Fc form (Pr20M) directed antibody-dependent cellular cytotoxicity against PRAME+HLA-A2+ leukemia cells and was therapeutically effective against mouse xenograft models of human leukemia. (sigmaaldrich.com)
  • In addition, it induced dose-dependent relative cytotoxicity against these lymphoma cells when incubated with PBMCs. (frontiersin.org)
  • For example, though chemotherapy could kill cancer cells through a cytotoxic treatment, it would also kill healthy cells and lead to a number of undesirable side effects. (biolegend.com)
  • The cancer-testis antigen NY-ESO-1 has been used as a target for different immunotherapies like vaccinations and adoptive transfer of antigen-specific cytotoxic T cells, as it is expressed in various tumor types and has limited expression in normal cells. (mdc-berlin.de)
  • When they come in contact with their targeted antigen on a cell, CAR-T cells bind to it and become activated, then proceed to proliferate and become cytotoxic. (wikipedia.org)
  • Prior to CAR-T cell infusion, cytotoxic chemotherapy may include cyclophosphamide and/or fludarabine. (urotoday.com)
  • When conjugated to Pseudomonas Exotoxin A (ETA´), the PCNSL reactive epitope exerts cytotoxic effects on lymphoma cells expressing a SAMD14/neurabin-I reactive BCR. (frontiersin.org)
  • Blinatumomab is superior to standard chemotherapy for children and young adults with high- or intermediate-risk B-cell acute lymphoblastic leukemia that has relapsed. (medworm.com)
  • Side effects experienced by participants were primarily related to the conditioning chemotherapy given before cell infusion and were resolved within one to two weeks, Rezvani said in the release. (curetoday.com)
  • 2 Fourth generation CARs, termed TRUCKS, add a proinflammatory factor such as IL-12 to provide higher tumor cell kill and potentially avoid the need for preparatory or conditioning chemotherapy. (urotoday.com)
  • Patients between greater than or equal to 3 years and less than or equal to 30 years of age, with CD19+/CD22+ B cell ALL or lymphoma who have relapsed or have refractory disease after at least one standard chemotherapy regimen and one salvage regimen, with no alternative curative options who meet standard Phase I eligibility criteria. (centerwatch.com)
  • Before the CAR T cells are infused into the bloodstream, the patient might need to undergo chemotherapy a few days before to reduce the number of other immune cells. (berkeleywellness.com)
  • Response rates for patients with B-cell neoplasms such as Non-Hodgkin's Lymphoma (NHL) and Acute Lymphoblastic Leukemia (ALL) treated with traditional modalities, including chemotherapy, radiation, and bone marrow transplant, are relatively high. (pulsus.com)
  • Prior to the patient being infused with the harvested CAR T cells, they may receive lymphodepleting chemotherapy to reduce the level of white blood cells and help the body accept the reprogrammed T cells. (lymphomacoalition.org)
  • May participate in suppression of cell proliferation and induces apoptotic cell death through activation of interleukin-1-beta converting enzyme (ICE)-like proteases. (uniprot.org)
  • Monitoring CAR T-cell polyfunctionality as a key product attribute may complement other characteristics including T-cell proliferation. (bloodjournal.org)
  • This may permit homeostatic proliferation of the infused T cells, eliminate competitive T cells that could serve as a "sink" for important activating cytokines, result in elimination of regulatory and suppressive T cells or even enhance endogenous host APC activity 8 . (jcancer.org)
  • This is a diagnostic hallmark of the disease and of high pathobiological relevance as cyclin D1 plays a major role in cell cycle control and therefore in proliferation (see below). (springermedizin.de)
  • l -Arg depletion by tumor-associated myeloid cells blocked the re-expression of CD3ζ in stimulated T cells and inhibited antigen-specific proliferation of OT-1 and OT-2 cells. (aacrjournals.org)
  • miR-18a Inhibitor Suppresses Leukemia Cell Proliferation by Upregulation of PTEN Expression. (physiciansweekly.com)
  • During this time, scientists were mainly limited to cells that could be taken from one animal and directly placed into another animal, but this changed over the next few decades, particularly after the discovery of IL-2 and its ability to help expand T cells in vitro prior to (and during) its injection into the host, amplifying the anti-tumor response from transfer. (biolegend.com)
  • In vitro studies using cultured human and mouse mast cells, and studies of mice lacking A 2B receptors, suggest that adenosine receptors, specifically the G s -coupled A 2A and A 2B receptors, might provide such a target. (aspetjournals.org)
  • Results showed that: (1) T cells that are specific for the p2Ca/L$\sp{\rm d}$ complex can be readily generated in vitro and (2) the T cells express a diverse TCR repertoire, although restrictions in the use of V$\beta$ and J$\beta$ regions were observed. (illinois.edu)
  • Tumor-associated myeloid cells also expressed high levels of cationic amino acid transporter 2B, which allowed them to rapidly incorporate l -Arginine ( l -Arg) and deplete extracellular l -Arg in vitro . (aacrjournals.org)
  • Lee, G. and Liu, S. (2013) Roles of antigen receptors and CA215 in the innate immunity of cancer cells. (scirp.org)
  • Taken together, we propose that hypoxia is a critical determinant of survival of the activated T cells via the HIF-1α-AM cascade, defining a previously unknown mode of regulation of peripheral immunity. (jimmunol.org)
  • Subsequently, accumulated T cells may need to be cleared away to prevent a harmful over-response or for preservation of homeostasis within the T cell compartment of peripheral immunity. (jimmunol.org)
  • Ideally, therapy for autoimmune diseases should eliminate pathogenic autoimmune cells while sparing protective immunity, but feasible strategies for such an approach have been elusive. (sciencemag.org)
  • The innate immunity of cancer cells can also be affected by any of these antibodies through unidirectional regulations of certain toll-like receptors. (omicsonline.org)
  • Therefore, the anti-cancer therapy of RP215 Mab may be, in part related to the surface bound antigen receptors and/or toll-like receptors in the innate immunity system, all of which may be involved in the growth and survival of cancer cells. (omicsonline.org)
  • Another approach in the development of immunotherapies is the use of cellular immunity with T cells. (lymphomacoalition.org)
  • Cellular immunity, also called cell-mediated immunity, is the response of the body's immune system to harmful invading foreign organisms. (lymphomacoalition.org)
  • These receptors have both extracellular and intracellular components. (medscape.com)
  • The CAR itself is a chimeric recombinant molecule that encompasses an extracellular antigen identification zone for Signal 1, a spacer, a transmembrane zone, and intracellular signaling moieties that facilitate Signal 2 costimulation and resultant signal transduction. (urotoday.com)
  • These data suggest that the region of V beta 3 encompassing amino acids 57-77 is an area that displays the appropriate sequence and conformation for binding of the SEA molecule and blocking of the resultant interaction with the T-cell antigen receptor. (pnas.org)
  • The CAR "generation" typically refers to the intracellular signaling domains incorporated in the receptor molecule. (frontiersin.org)
  • Molecular model of the alphabeta T cell receptor bound to the influenza haemagglutinin antigen and MHC class II molecule HLA-DR1. (sciencephoto.com)
  • A and B) The μ-High and μ-Low J558L cells labeled with Alexa Fluor 568-Fab anti-IgM were placed on planar lipid bilayers lacking antigen (A) or containing NIP1-His12 (B), and single BCR molecule TIRF images were acquired. (rupress.org)
  • They do this by adding an artificial chimeric antigen receptor, which locks on to a matching molecule on cancer cells. (berkeleywellness.com)
  • First-generation CARs typically utilized the intracellular domain of the CD3z chain only, the primary signaling molecule from endogenous T-cell receptors. (jcancer.org)
  • The signaling lymphocyte activation molecule-related receptor 2B4 (CD244) is an important regulator of NK cell activation. (aacrjournals.org)
  • Campoli M, Ferrone S. HLA antigen changes in malignant cells: epigenetic mechanisms and biologic significance. (springer.com)
  • Potentially malignant cells are continuously eliminated by apoptosis and the immune system, but cancers have escaped these mechanisms. (bloodjournal.org)
  • These trials ultimately led to the first FDA approvals of CAR T cells in 2017 for tisagenlecleucel (Kymriah), marketed by Novartis originally for B-cell acute lymphoblastic leukemia (B-ALL), and axicabtagene ciloleucel (Yescarta), marketed by Kite Pharma originally for Diffuse Large B-cell lymphoma (DLBCL). (wikipedia.org)
  • In this study, the researchers administered a single dose of the CAR NK-cell therapy at one of three dose levels to 11 patients - five of whom had chronic lymphocytic leukemia (CLL) and six who were diagnosed with non-Hodgkin lymphoma. (curetoday.com)
  • Early studies with CAR-T cell therapy showed impressive efficacy in chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), and refractory B cell lymphoma. (urotoday.com)
  • After treatment with chimeric antigen receptor (CAR) T cells, interleukin (IL)-15 elevation and CAR T-cell expansion are associated with non-Hodgkin lymphoma (NHL) outcomes. (bloodjournal.org)
  • In the study , led by the National Cancer Institute, 101 adult patients with an aggressive form of B-cell lymphoma underwent CAR T-cell therapy. (berkeleywellness.com)
  • To target this antigen, CAR T cells have gained great success in treating patients with B cell leukemia and lymphoma. (eurekaselect.com)
  • The past two decades of lymphoma research have uncovered the essential role of the B-cell antigen receptor (BCR) pathway in lymphoma biology. (haematologica.org)
  • This post-translational modification of neurabin-I and SAMD14 seems to lead to a chronic immune reaction with B-cell receptor activation contributing to lymphoma genesis of PCNSLs. (frontiersin.org)
  • Specific binding of the prokaryotically produced SAMD14/neurabin-I Fab-antibody to lymphoma cells and their internalization were determined by flow cytometry. (frontiersin.org)
  • The IgG1-format SAMD14/neurabin-I construct was found to specifically bind to target lymphoma cells expressing a SAMD14/neurabin-I reactive B cell receptor. (frontiersin.org)
  • Over time, FL could acquire additional genetic mutations and transform into diffuse large B-cell lymphoma, a more aggressive B-cell neoplasm, which markedly reduces survival. (medworm.com)
  • At the University of Pennsylvania alone, Dr. Schuster said more than 200 patients had been treated with CAR T-cell therapy when factoring in the patients with acute lymphocytic leukaemia as well as those with lymphoma. (lymphomacoalition.org)
  • CAR T Cells: Engineering Patients' Immune Cells to Treat Their Cancers. (medscape.com)
  • Smith AJ, Oertle J, Warren D, Prato D. Chimeric antigen receptor (CAR) T cell therapy for malignant cancers: summary and perspective. (springer.com)
  • Targeted drugs, such as monoclonal antibodies directed at specific tumor antigens, made a big impact on how cancers were treated in that they could attack transformed cells while leaving the healthy cells alone. (biolegend.com)
  • However, these were still limited in that the treatments were very specific to a particular tumor cell type, and thus could only treat certain cancers (and sometimes, only very rare cancers). (biolegend.com)
  • The first major driving force to treating cancers through ACT was the discovery in the mid 1960s that immune cells were responsible for tissue transplant rejection, or graft-versus-host disease (GVHD). (biolegend.com)
  • CMS initiates this national coverage analysis for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers. (cms.gov)
  • Preferentially expressed antigen in melanoma (PRAME) is a cancer-testis antigen that is expressed in many cancers and leukemias. (sigmaaldrich.com)
  • B-cell leukemias and lymphomas are cancers that are often difficult to treat. (centerwatch.com)
  • those included three people whose cancers spread beyond the blood cells the new treatment targets. (fightaging.org)
  • Technology potentially provides compositions and methods for prophylaxis and/or therapy for a variety of cancers which express a NY-ESO-1 antigen. (roswellpark.org)
  • Human papilloma virus (HPV)-targeted T cell therapy for patients with HPV-associated cancers / Christian S. Hinrichs. (nih.gov)
  • Roswell researchers have discovered that there are two distinct types of tumor antigen-specific CD4+ T cells. (roswellpark.org)
  • A part of tumor antigen-specific CD4+ T cells, that we named "tumor-recognizing CD4+ T cells (TR-CD4)", directly recognizes MHC class II-expressing cancer cells in antigen-specific and MHC class II-restricted manners. (roswellpark.org)
  • Jordan, M.S., Singer, A.L. & Koretzky, G.A. Adaptors as central mediators of signal transduction in immune cells. (nature.com)
  • Lim WA, June CH. The principles of engineering immune cells to treat cancer. (springer.com)
  • In the 1980s, Dr. Zelig Eshhar and his lab thought of the idea of altering immune cells prior to adoptive transfer so that they could more specifically target tumor cells. (biolegend.com)
  • Transferring large amounts of overactive immune cells does have some negative consequences. (biolegend.com)
  • Trogocytosis is a process in which membrane patches are exchanged between target and immune cells [5] - [7] . (plos.org)
  • Because the therapy consists of living immune cells, it represents something truly revolutionary: a living drug. (berkeleywellness.com)
  • A trial has been running in leukemia patients using immune cells modified to express a variety of chimeric antigen receptors . (fightaging.org)
  • Recently, chimeric antigen receptor-modified T- (CART-) cell-based therapy, an innovative approach to tumor treatment, was demonstrated to potentially exhibit MHC-independent antitumor effects. (hindawi.com)
  • Affinity-tuned cells exhibited robust antitumor efficacy similar to high-affinity cells, but spared normal cells expressing physiologic target levels. (aacrjournals.org)
  • 3. Studies on the average avidity of the antibody produced by specific plaque-forming cells. (nature.com)
  • Liu, Y. J., Oldfield, S. & MacLennan, I. C. Memory B cells in T cell-dependent antibody responses colonize the splenic marginal zones. (nature.com)
  • CARs have a single-chain variable fragment (scFv), which is derived from the part of an antibody that is specific to an antigen. (biolegend.com)
  • Recently, a monoclonal antibody, designated as RP215, was generated against the ovarian cancer cell line, OC-3-VGH, and was shown to react with CA215, which consisted mainly of these cancer cell-expressed antigen receptors. (scirp.org)
  • Anti-θAKR antibody conjugated to fluorescein has been used in direct immunofluorescence tests to identify spleen θ + (T) sheep erythrocyte rosette-forming cells in AKR mice. (rupress.org)
  • When given to diseased mice, the engineered T cells targeted and killed B cells that express antibodies targeting desmoglein 3, hinting that such a strategy may be an effective way to treat antibody-driven autoimmune diseases. (sciencemag.org)
  • CAAR-T cells may provide an effective and universal strategy for specific targeting of autoreactive B cells in antibody-mediated autoimmune disease. (sciencemag.org)
  • The SAMD14/neurabin-I Fab antibody bound specifically to DLBCL cells expressing a BCR with reactivity to SAMD14/neurabin-I and not to unmanipulated DLBCL cell lines. (frontiersin.org)
  • RP215 is a monoclonal antibody (Mab) generated against an ovarian cancer cell line, OC-3-VGH in 1987 and shown to react with the carbohydrate-associated epitope of glycoproteins known as CA215 expressed by cancer cells [ 1 , 2 ]. (omicsonline.org)
  • Whereas the antibody uses its Fc region to bind to Fc Receptors on leukocytes, TCR is already docked onto the cell membrane. (wikipedia.org)
  • For safety, CAR-T cells are engineered to be specific to an antigen expressed on a tumor that is not expressed on healthy cells. (wikipedia.org)
  • Furthermore, selected toll-like receptor genes (TLR- 2, -3, -4, and -9) were also found to be highly regulated by both RP215 and anti-antigen receptor antibodies. (scirp.org)
  • For example, RP215 and anti-antigen receptor antibodies were found to both up-regulate TLR-2 and/or TLR-3 and down- regulate TLR-4 and TLR-9 intwo types of cancer cells. (scirp.org)
  • For both cell lines, RP215 and anti-antigen receptors were found to regulate similarly and consistently a number of genes including NFκB-1, IgG, P21, Cyclin D1, ribosomal P1 and c-fos with only exceptions for EGFR and ribosomal P0. (omicsonline.org)
  • Based on these preliminary observations, it can be proposed that apoptosis of the two cancer cell lines was induced similarly by RP215 and anti-antigen receptors through consistent regulations of the same groups of genes. (omicsonline.org)
  • In addition to antigen-presenting cells such as macrophages and dendritic cells, many human cancer cells express MHC class II constitutively or in an IFN-γ-inducible manner although the role of MHC class II expression on human cancer cells is largely unknown. (roswellpark.org)