Antigens: Substances that are recognized by the immune system and induce an immune reaction.Antigens, Bacterial: Substances elaborated by bacteria that have antigenic activity.Immunoconjugates: 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.CTLA-4 Antigen: 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.Antigens, Neoplasm: 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, Surface: 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.Antigens, Viral: Substances elaborated by viruses that have antigenic activity.Antigens, CD: 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.Antigens, Protozoan: Any part or derivative of any protozoan that elicits immunity; malaria (Plasmodium) and trypanosome antigens are presently the most frequently encountered.Antigens, Polyomavirus Transforming: 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.HLA Antigens: 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.Antigens, Fungal: Substances of fungal origin that have antigenic activity.Antigens, Helminth: Any part or derivative of a helminth that elicits an immune reaction. The most commonly seen helminth antigens are those of the schistosomes.H-2 Antigens: The major group of transplantation antigens in the mouse.Antigens, CD80: 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.Antibodies, Monoclonal: Antibodies produced by a single clone of cells.Carcinoembryonic Antigen: 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.Antigens, Viral, Tumor: 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.Antigens, CD28: 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.T-Lymphocytes: 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.Receptors, Antigen, T-Cell: 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.HLA-DR Antigens: 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.Histocompatibility Antigens: 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.Proliferating Cell Nuclear Antigen: 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.Histocompatibility Antigens Class II: 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.Lymphocyte Activation: 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.Antigens, CD86: 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.Prostate-Specific Antigen: 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.O Antigens: 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)Receptors, Antigen, B-Cell: 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.Epitopes: Sites on an antigen that interact with specific antibodies.Mice, Inbred BALB CAntigens, CD15: 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.Enzyme-Linked Immunosorbent Assay: 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.Antigens, Tumor-Associated, Carbohydrate: 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.Antigens, CD3: 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).HLA-A2 Antigen: A specific HLA-A surface antigen subtype. Members of this subtype contain alpha chains that are encoded by the HLA-A*02 allele family.Immunoglobulin G: The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of IgG, for example, IgG1, IgG2A, and IgG2B.Antigens, CD8: 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.Blood Group Antigens: Sets of cell surface antigens located on BLOOD CELLS. They are usually membrane GLYCOPROTEINS or GLYCOLIPIDS that are antigenically distinguished by their carbohydrate moieties.Hepatitis B Surface Antigens: 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.Cross Reactions: Serological reactions in which an antiserum against one antigen reacts with a non-identical but closely related antigen.Molecular Sequence Data: 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.Antigens, CD45: 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.Antigens, CD4: 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.HLA-A Antigens: 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.Histocompatibility Antigens Class I: 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.Mice, Inbred C57BLAntibody Formation: The production of ANTIBODIES by proliferating and differentiated B-LYMPHOCYTES under stimulation by ANTIGENS.HLA-D Antigens: 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.Antibody Specificity: 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.Receptors, Antigen: Molecules on the surface of B- and T-lymphocytes that recognize and combine with specific antigens.Hepatitis B Antigens: 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.B-Lymphocytes: 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.Immune Tolerance: 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.Antigen-Antibody Reactions: The processes triggered by interactions of ANTIBODIES with their ANTIGENS.Cell Line: Established cell cultures that have the potential to propagate indefinitely.Immunization: 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).Antigens, CD40: 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.Antigens, CD1: 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.Fluorescent Antibody Technique: 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.Amino Acid Sequence: 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.Antibodies, Bacterial: Immunoglobulins produced in a response to BACTERIAL ANTIGENS.Immune Sera: 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.Spleen: An encapsulated lymphatic organ through which venous blood filters.HLA-B Antigens: 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.Antigens, Differentiation: 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.Dendritic Cells: 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).CD4-Positive T-Lymphocytes: 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.Antibodies: 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).Flow Cytometry: 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.MART-1 Antigen: 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.Membrane Glycoproteins: Glycoproteins found on the membrane or surface of cells.HIV Antigens: 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.Antigen-Presenting Cells: A heterogeneous group of immunocompetent cells that mediate the cellular immune response by processing and presenting antigens to the T-cells. Traditional antigen-presenting cells include MACROPHAGES; DENDRITIC CELLS; LANGERHANS CELLS; and B-LYMPHOCYTES. FOLLICULAR DENDRITIC CELLS are not traditional antigen-presenting cells, but because they hold antigen on their cell surface in the form of IMMUNE COMPLEXES for B-cell recognition they are considered so by some authors.Cells, Cultured: 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.Interferon-gamma: 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.T-Lymphocytes, Cytotoxic: 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.Autoantigens: Endogenous tissue constituents that have the ability to interact with AUTOANTIBODIES and cause an immune response.Epstein-Barr Virus Nuclear Antigens: Nuclear antigens encoded by VIRAL GENES found in HUMAN HERPESVIRUS 4. At least six nuclear antigens have been identified.Immunoenzyme Techniques: 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.Ovalbumin: An albumin obtained from the white of eggs. It is a member of the serpin superfamily.Antigens, CD19: Differentiation antigens expressed on B-lymphocytes and B-cell precursors. They are involved in regulation of B-cell proliferation.Isoantigens: 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.Base Sequence: The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.Antigens, Heterophile: Antigens stimulating the formation of, or combining with heterophile antibodies. They are cross-reacting antigens found in phylogenetically unrelated species.Hepatitis B Core Antigens: The hepatitis B antigen within the core of the Dane particle, the infectious hepatitis virion.Immunosuppressive Agents: Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of T-CELLS or by inhibiting the activation of HELPER CELLS. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of INTERLEUKINS and other CYTOKINES are emerging.CD8-Positive T-Lymphocytes: 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.Inducible T-Cell Co-Stimulator Protein: A costimulatory receptor that is specific for INDUCIBLE T-CELL CO-STIMULATOR LIGAND. The receptor is associated with a diverse array of immunologically-related effects including the increased synthesis of INTERLEUKIN 10 in REGULATORY T-LYMPHOCYTES and the induction of PERIPHERAL TOLERANCE.Immunodiffusion: Technique involving the diffusion of antigen or antibody through a semisolid medium, usually agar or agarose gel, with the result being a precipitin reaction.Immunoglobulin M: 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.Antigens, Thy-1: 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.Forssman Antigen: A glycolipid, cross-species antigen that induces production of antisheep hemolysin. It is present on the tissue cells of many species but absent in humans. It is found in many infectious agents.HLA-B7 Antigen: A specific HLA-B surface antigen subtype. Members of this subtype contain alpha chains that are encoded by the HLA-B*07 allele family.Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes IMMUNE COMPLEX DISEASES.Lymphocyte Culture Test, Mixed: 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.Immunity, Cellular: 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.Lymphocytes: 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.H-Y Antigen: 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.Molecular Weight: The sum of the weight of all the atoms in a molecule.Graft Survival: The survival of a graft in a host, the factors responsible for the survival and the changes occurring within the graft during growth in the host.Antibodies, Viral: Immunoglobulins produced in response to VIRAL ANTIGENS.Autoantibodies: Antibodies that react with self-antigens (AUTOANTIGENS) of the organism that produced them.Transplantation, Homologous: Transplantation between individuals of the same species. Usually refers to genetically disparate individuals in contradistinction to isogeneic transplantation for genetically identical individuals.Complement Fixation Tests: Serologic tests based on inactivation of complement by the antigen-antibody complex (stage 1). Binding of free complement can be visualized by addition of a second antigen-antibody system such as red cells and appropriate red cell antibody (hemolysin) requiring complement for its completion (stage 2). Failure of the red cells to lyse indicates that a specific antigen-antibody reaction has taken place in stage 1. If red cells lyse, free complement is present indicating no antigen-antibody reaction occurred in stage 1.HLA-DQ Antigens: 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.Graft Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient.Simian virus 40: A species of POLYOMAVIRUS originally isolated from Rhesus monkey kidney tissue. It produces malignancy in human and newborn hamster kidney cell cultures.Interleukin-2: A soluble substance elaborated by antigen- or mitogen-stimulated T-LYMPHOCYTES which induces DNA synthesis in naive lymphocytes.Dose-Response Relationship, Immunologic: A specific immune response elicited by a specific dose of an immunologically active substance or cell in an organism, tissue, or cell.Major Histocompatibility Complex: 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.Recombinant Fusion Proteins: 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.Receptors, Antigen, T-Cell, alpha-beta: 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.Mice, Inbred Strains: 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.Rabbits: The species Oryctolagus cuniculus, in the family Leporidae, order LAGOMORPHA. Rabbits are born in burrows, furless, and with eyes and ears closed. In contrast with HARES, rabbits have 22 chromosome pairs.CD40 Ligand: 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.Immunoelectrophoresis: A technique that combines protein electrophoresis and double immunodiffusion. In this procedure proteins are first separated by gel electrophoresis (usually agarose), then made visible by immunodiffusion of specific antibodies. A distinct elliptical precipitin arc results for each protein detectable by the antisera.Recombinant Proteins: Proteins prepared by recombinant DNA technology.Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents.Mice, Inbred C3HImmunoglobulin Fc Fragments: Crystallizable fragments composed of the carboxy-terminal halves of both IMMUNOGLOBULIN HEAVY CHAINS linked to each other by disulfide bonds. Fc fragments contain the carboxy-terminal parts of the heavy chain constant regions that are responsible for the effector functions of an immunoglobulin (COMPLEMENT fixation, binding to the cell membrane via FC RECEPTORS, and placental transport). This fragment can be obtained by digestion of immunoglobulins with the proteolytic enzyme PAPAIN.Cytotoxicity, Immunologic: 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.Rats, Inbred LewAntigens, CD79: A component of the B-cell antigen receptor that is involved in B-cell antigen receptor heavy chain transport to the PLASMA MEMBRANE. It is expressed almost exclusively in B-LYMPHOCYTES and serves as a useful marker for B-cell NEOPLASMS.Antibodies, Protozoan: Immunoglobulins produced in a response to PROTOZOAN ANTIGENS.CA-19-9 Antigen: Sialylated Lewis blood group carbohydrate antigen found in many adenocarcinomas of the digestive tract, especially pancreatic tumors.Isoantibodies: Antibodies from an individual that react with ISOANTIGENS of another individual of the same species.Genetic Vectors: DNA molecules capable of autonomous replication within a host cell and into which other DNA sequences can be inserted and thus amplified. Many are derived from PLASMIDS; BACTERIOPHAGES; or VIRUSES. They are used for transporting foreign genes into recipient cells. Genetic vectors possess a functional replicator site and contain GENETIC MARKERS to facilitate their selective recognition.Mice, Transgenic: Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN.Hemagglutination Tests: Sensitive tests to measure certain antigens, antibodies, or viruses, using their ability to agglutinate certain erythrocytes. (From Stedman, 26th ed)gp100 Melanoma Antigen: A melanosome-associated protein that plays a role in the maturation of the MELANOSOME.Serologic Tests: Diagnostic procedures involving immunoglobulin reactions.Lewis Blood-Group System: A group of dominantly and independently inherited antigens associated with the ABO blood factors. They are glycolipids present in plasma and secretions that may adhere to the erythrocytes. The phenotype Le(b) is the result of the interaction of the Le gene Le(a) with the genes for the ABO blood groups.Skin Transplantation: The grafting of skin in humans or animals from one site to another to replace a lost portion of the body surface skin.Immunosuppression: Deliberate prevention or diminution of the host's immune response. It may be nonspecific as in the administration of immunosuppressive agents (drugs or radiation) or by lymphocyte depletion or may be specific as in desensitization or the simultaneous administration of antigen and immunosuppressive drugs.Ki-67 Antigen: A CELL CYCLE and tumor growth marker which can be readily detected using IMMUNOCYTOCHEMISTRY methods. Ki-67 is a nuclear antigen present only in the nuclei of cycling cells.Antibodies, Helminth: Immunoglobulins produced in a response to HELMINTH ANTIGENS.Autoimmune Diseases: Disorders that are characterized by the production of antibodies that react with host tissues or immune effector cells that are autoreactive to endogenous peptides.Antigens, T-Independent: Antigens which may directly stimulate B lymphocytes without the cooperation of T lymphocytes.Cytokines: 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.Sensitivity and Specificity: Binary classification measures to assess test results. Sensitivity or recall rate is the proportion of true positives. Specificity is the probability of correctly determining the absence of a condition. (From Last, Dictionary of Epidemiology, 2d ed)Antigens, CD2: 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.Time Factors: Elements of limited time intervals, contributing to particular results or situations.Hepatitis B e Antigens: A closely related group of antigens found in the plasma only during the infective phase of hepatitis B or in virulent chronic hepatitis B, probably indicating active virus replication; there are three subtypes which may exist in a complex with immunoglobulins G.Lymph Nodes: They are oval or bean shaped bodies (1 - 30 mm in diameter) located along the lymphatic system.Electrophoresis, Polyacrylamide Gel: Electrophoresis in which a polyacrylamide gel is used as the diffusion medium.Hypersensitivity, Delayed: An increased reactivity to specific antigens mediated not by antibodies but by cells.Antigens, CD95: 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.CA-125 Antigen: Carbohydrate antigen most commonly seen in tumors of the ovary and occasionally seen in breast, kidney, and gastrointestinal tract tumors and normal tissue. CA 125 is clearly tumor-associated but not tumor-specific.Adenoviridae: A family of non-enveloped viruses infecting mammals (MASTADENOVIRUS) and birds (AVIADENOVIRUS) or both (ATADENOVIRUS). Infections may be asymptomatic or result in a variety of diseases.Antigens, Nuclear: Immunologically detectable substances found in the CELL NUCLEUS.T-Lymphocytes, Regulatory: 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.Minor Histocompatibility Antigens: 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.Adjuvants, Immunologic: 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.Hybridomas: 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.HLA-B27 Antigen: A specific HLA-B surface antigen subtype. Members of this subtype contain alpha chains that are encoded by the HLA-B*27 allele family.Melanoma: A malignant neoplasm derived from cells that are capable of forming melanin, which may occur in the skin of any part of the body, in the eye, or, rarely, in the mucous membranes of the genitalia, anus, oral cavity, or other sites. It occurs mostly in adults and may originate de novo or from a pigmented nevus or malignant lentigo. Melanomas frequently metastasize widely, and the regional lymph nodes, liver, lungs, and brain are likely to be involved. The incidence of malignant skin melanomas is rising rapidly in all parts of the world. (Stedman, 25th ed; from Rook et al., Textbook of Dermatology, 4th ed, p2445)Immunoassay: A technique using antibodies for identifying or quantifying a substance. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance.Clone Cells: 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)Hepatitis delta Antigens: Antigens produced by various strains of HEPATITIS D VIRUS.Blotting, Western: Identification of proteins or peptides that have been electrophoretically separated by blot transferring from the electrophoresis gel to strips of nitrocellulose paper, followed by labeling with antibody probes.T-Lymphocyte Subsets: A classification of T-lymphocytes, especially into helper/inducer, suppressor/effector, and cytotoxic subsets, based on structurally or functionally different populations of cells.HLA-C Antigens: Class I human histocompatibility (HLA) antigens encoded by a small cluster of structural genes at the C locus on chromosome 6. They have significantly lower immunogenicity than the HLA-A and -B determinants and are therefore of minor importance in donor/recipient crossmatching. Their primary role is their high-risk association with certain disease manifestations (e.g., spondylarthritis, psoriasis, multiple myeloma).Mice, Inbred CBAAntigens, CD58: Glycoproteins with a wide distribution on hematopoietic and non-hematopoietic cells and strongly expressed on macrophages. CD58 mediates cell adhesion by binding to CD2; (ANTIGENS, CD2); and this enhances antigen-specific T-cell activation.Antigens, CD1d: A major histocompatibily complex class I-like protein that plays a unique role in the presentation of lipid ANTIGENS to NATURAL KILLER T-CELLS.HLA-A1 Antigen: A specific HLA-A surface antigen subtype. Members of this subtype contain alpha chains that are encoded by the HLA-A*01 allele family.Peptides: 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.Polysaccharides, Bacterial: Polysaccharides found in bacteria and in capsules thereof.HLA-DR4 Antigen: An HLA-DR antigen which is associated with HLA-DRB1 CHAINS encoded by DRB1*04 alleles.Cloning, Molecular: The insertion of recombinant DNA molecules from prokaryotic and/or eukaryotic sources into a replicating vehicle, such as a plasmid or virus vector, and the introduction of the resultant hybrid molecules into recipient cells without altering the viability of those cells.HLA-DR3 Antigen: An HLA-DR antigen which is associated with HLA-DRB1 CHAINS encoded by DRB1*03 alleles.ABO Blood-Group System: The major human blood type system which depends on the presence or absence of two antigens A and B. Type O occurs when neither A nor B is present and AB when both are present. A and B are genetic factors that determine the presence of enzymes for the synthesis of certain glycoproteins mainly in the red cell membrane.Protein Tyrosine Phosphatase, Non-Receptor Type 22: A subtype of non-receptor protein tyrosine phosphatases that is characterized by the presence of an N-terminal catalytic domain and a C-terminal PROLINE-rich domain. The phosphatase subtype is predominantly expressed in LYMPHOCYTES and plays a key role in the inhibition of downstream T-LYMPHOCYTE activation. Polymorphisms in the gene that encodes this phosphatase subtype are associated with a variety of AUTOIMMUNE DISEASES.Agglutination Tests: Tests that are dependent on the clumping of cells, microorganisms, or particles when mixed with specific antiserum. (From Stedman, 26th ed)Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by AUTOIMMUNE DISEASES.Vaccines, Synthetic: Small synthetic peptides that mimic surface antigens of pathogens and are immunogenic, or vaccines manufactured with the aid of recombinant DNA techniques. The latter vaccines may also be whole viruses whose nucleic acids have been modified.Polymerase Chain Reaction: 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.Antigens, CD5: 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)B7 Antigens: A family of cell-surface proteins found on ANTIGEN-PRESENTING CELLS. B7 antigens are ligands for specific cell surface receptor subtypes found on T-CELLS. They play an immunomodulatory role by stimulating or inhibiting the T-CELL activation process.Prostatic Neoplasms: Tumors or cancer of the PROSTATE.Antigens, CD20: Unglycosylated phosphoproteins expressed only on B-cells. They are regulators of transmembrane Ca2+ conductance and thought to play a role in B-cell activation and proliferation.Antigens, CD27: 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.Immunoglobulins: 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.HLA-A24 Antigen: A specific HLA-A surface antigen subtype. Members of this subtype contain alpha chains that are encoded by the HLA-A*24 allele family.Immunologic Memory: 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, CD34: Glycoproteins found on immature hematopoietic cells and endothelial cells. They are the only molecules to date whose expression within the blood system is restricted to a small number of progenitor cells in the bone marrow.Binding Sites, Antibody: Local surface sites on antibodies which react with antigen determinant sites on antigens (EPITOPES.) They are formed from parts of the variable regions of FAB FRAGMENTS.Cancer Vaccines: 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.Injections, Intralymphatic: Injections into the lymph nodes or the lymphatic system.Antibody Affinity: A measure of the binding strength between antibody and a simple hapten or antigen determinant. It depends on the closeness of stereochemical fit between antibody combining sites and antigen determinants, on the size of the area of contact between them, and on the distribution of charged and hydrophobic groups. It includes the concept of "avidity," which refers to the strength of the antigen-antibody bond after formation of reversible complexes.Vaccination: Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis.Cell Division: The fission of a CELL. It includes CYTOKINESIS, when the CYTOPLASM of a cell is divided, and CELL NUCLEUS DIVISION.Tumor Cells, Cultured: 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.Antibodies, Blocking: Antibodies that inhibit the reaction between ANTIGEN and other antibodies or sensitized T-LYMPHOCYTES (e.g., antibodies of the IMMUNOGLOBULIN G class that compete with IGE antibodies for antigen, thereby blocking an allergic response). Blocking antibodies that bind tumors and prevent destruction of tumor cells by CYTOTOXIC T-LYMPHOCYTES have also been called enhancing antibodies. (Rosen et al., Dictionary of Immunology, 1989)Transfection: 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.Glycoproteins: Conjugated protein-carbohydrate compounds including mucins, mucoid, and amyloid glycoproteins.Heart Transplantation: The transference of a heart from one human or animal to another.Bacterial Proteins: Proteins found in any species of bacterium.Phenotype: The outward appearance of the individual. It is the product of interactions between genes, and between the GENOTYPE and the environment.

The CTLA-4 gene is expressed in placental fibroblasts. (1/1386)

In order to elucidate the mechanisms that ensure survival of the allogeneic fetus, we are investigating the expression pattern of genes that are involved in peripheral self-tolerance in tissues at the maternal-fetal interface. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a negative regulator of T cell activation and may modulate peripheral self-tolerance. Previously, we reported the preferential transmission of maternally-inherited shorter alleles at a 3'-UTR microsatellite locus to liveborn children, but random transmission of paternally-inherited alleles, suggesting that CTLA-4 may be involved in the maintenance of tolerance at the maternal-fetal interface. In this report, we demonstrate that CTLA-4 mRNA and protein are indeed expressed in fetal tissues at the maternal-fetal interface throughout gestation.  (+info)

Cellular and molecular characterization of the scurfy mouse mutant. (2/1386)

Mice hemizygous (Xsf/Y) for the X-linked mutation scurfy (sf) develop a severe and rapidly fatal lymphoproliferative disease mediated by CD4+CD8- T lymphocytes. We have undertaken phenotypic and functional studies to more accurately identify the immunologic pathway(s) affected by this important mutation. Flow cytometric analyses of lymphoid cell populations reveal that scurfy syndrome is characterized by changes in several phenotypic parameters, including an increase in Mac-1+ cells and a decrease in B220+ cells, changes that may result from the production of extremely high levels of the cytokine granulocyte-macrophage CSF by scurfy T cells. Scurfy T cells also exhibit strong up-regulation of cell surface Ags indicative of in vivo activation, including CD69, CD25, CD80, and CD86. Both scurfy and normal T cells are responsive to two distinct signals provided by the TCR and by ligation of CD28; scurfy cells, however, are hyperresponsive to TCR ligation and exhibit a decreased requirement for costimulation through CD28 relative to normal controls. This hypersensitivity may result, in part, from increased costimulation through B7-1 and B7-2, whose expression is up-regulated on scurfy T cells. Although the specific defect leading to this hyperactivation has not been identified, we also demonstrate that scurfy T cells are less sensitive than normal controls to inhibitors of tyrosine kinases such as genistein and herbimycin A, and the immunosuppressant cyclosporin A. One interpretation of our data would suggest that the scurfy mutation results in a defect, which interferes with the normal down-regulation of T cell activation.  (+info)

Experimental murine schistosomiasis in the absence of B7 costimulatory molecules: reversal of elicited T cell cytokine profile and partial inhibition of egg granuloma formation. (3/1386)

The granulomatous inflammation in infection with the helminth Schistosoma mansoni represents a cellular hypersensitivity reaction mediated by, and dependent upon, MHC class II-restricted CD4+ Th cells sensitized to parasite egg Ags. The current work examines the role and significance of the B7:CD28/CTLA-4 pathway in providing the costimulation necessary for the activation of these pathogenic T cells. In vitro T cell responses in B7-1-/- mice, 7-8 wk postinfection, were no different from wild-type controls, but the absence of B7-2 molecules resulted in a decrease in egg Ag-induced proliferation with increased IFN-gamma production. Both B7-1-/- and B7-2-/- mice exhibited intact granuloma formation. In contrast, CD4+ Th cells from B7-1/2 double-deficient mice displayed a dramatic loss of proliferative capacity upon stimulation with egg Ag. Most strikingly, these T cells secreted only IFN-gamma, but not IL-4 and IL-10, a pattern entirely opposite to that displayed by wild-type controls. Despite these major differences in T cell reactivity, B7-1/2-/- mice had only a limited reduction of granuloma size and fibrosis, without appreciable difference in cellular composition. These results show that substantial granuloma formation can occur under conditions of limited T cell expansion and restricted Th1-type cytokine production. They also support the notion that the combined effect of B7 signaling is not as critical for Th1 cell activation as it is for the development of the Th2 dominant environment characteristic of the evolving schistosome infection in H-2b mice.  (+info)

Prevention of autoimmune recurrence and rejection by adenovirus-mediated CTLA4Ig gene transfer to the pancreatic graft in BB rat. (4/1386)

Type 1 diabetes is the result of a selective destruction of pancreatic islets by autoreactive T-cells. Therefore, in the context of islet or pancreas transplantation, newly transplanted beta-cells are threatened by both recurrent autoimmune and alloimmune responses in recipients with type 1 diabetes. In the present study, using spontaneously diabetic BB rats, we demonstrate that whereas isolated islets are susceptible to autoimmune recurrence and rejection, pancreaticoduodenal grafts are resistant to these biological processes. This resistance is mediated by lymphohematopoietic cells transplanted with the graft, since inactivation of these passenger cells by irradiation uniformly rendered the pancreaticoduodenal grafts susceptible to recurrent autoimmunity. We further studied the impact of local immunomodulation on autoimmune recurrence and rejection by ex vivo adenovirus-mediated CTLA4Ig gene transfer to pancreaticoduodenal grafts. Syngeneic DR-BB pancreaticoduodenal grafts transduced with AdmCTLA4Ig were rescued from recurrent autoimmunity. In fully histoincompatible LEW-->BB transplants, in which rejection and recurrence should be able to act synergistically, AdmCTLA4Ig transduced LEW-pancreaticoduodenal allografts enjoyed markedly prolonged survival in diabetic BB recipients. In situ reverse transcription-polymerase chain reaction revealed that transferred CTLA4Ig gene was strongly expressed in both endocrine and exocrine tissues on day 3. These results indicate the potential utility of local CD28-B7 costimulatory blockade for prevention of alloimmune and autoimmune destruction of pancreatic grafts in type 1 diabetic hosts.  (+info)

Phenotypic analysis of lymphocytes and monocytes/macrophages in peripheral blood and bronchoalveolar lavage fluid from patients with pulmonary sarcoidosis. (5/1386)

BACKGROUND: The granulomatous inflammation in sarcoidosis is driven by the interplay between T cells and macrophages. To gain a better understanding of this process the expression by these cells of cell surface activation markers, co-stimulatory molecules, and adhesion molecules was analysed. METHODS: CD4+ and CD8+ T lymphocytes from peripheral blood (PBL) or bronchoalveolar lavage (BAL) fluid, as well as paired peripheral blood monocytes and alveolar macrophages from 27 patients with sarcoidosis were analysed by flow cytometry. RESULTS: CD26, CD54, CD69, CD95, and gp240 were all overexpressed in T cells from BAL fluid compared with those from PBL in both the CD4+ and CD8+ subsets, while CD57 was overexpressed only in BAL CD4+ cells. In contrast, CD28 tended to be underexpressed in the BAL T cells. Monocyte/macrophage markers included CD11a, CD11b, CD11c, CD14, CD16, CD54, CD71, CD80 and CD86 and HLA class II. CD11a expression in alveolar macrophages (and peripheral blood monocytes) was increased in patients with active disease and correlated positively with the percentage of BAL lymphocytes. Expression of CD80 in macrophages correlated with the BAL CD4/CD8 ratio. CONCLUSIONS: Our data indicate substantial activation of both CD4+ and CD8+ lung T cells in sarcoidosis. There were also increased numbers of BAL lymphocytes whose phenotypic characteristics have earlier been associated with clonally expanded, replicatively senescent cells of the Th1 type.  (+info)

The role of CTLA-4 in the regulation of T cell immune responses. (6/1386)

Over the past few years a great deal of research has examined how T cell-dependent immune responses are initiated and subsequently regulated. Ligation of the TCR with an antigenic peptide bound to an MHC protein on a professional APC provides the crucial antigen-specific stimulus required for T cell activation. Interaction of CD28 with CD80 or CD86 molecules on APC initiates a costimulatory or second signal within the T cell which augments and sustains T cell activation initiated through the TCR. However, recently it has become clear that T cell immune responses are a result of a balance between stimulatory and inhibitory signals. Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) is a cell surface molecule that is expressed nearly exclusively on CD4+ and CD8+ T cells. Investigation into the role of CTLA-4 in the regulation of T cell immune responses has revealed that CTLA-4 is a very important molecule involved in the maintenance of T cell homeostasis. In the present review, evidence for the proposed inhibitory role of CTLA-4 is examined and a model suggesting a role for CTLA-4 in both early and late stages of T cell activation is presented.  (+info)

CTLA-4 gene polymorphism is associated with predisposition to coeliac disease. (7/1386)

BACKGROUND: Susceptibility to coeliac disease is strongly associated with particular HLA class II alleles. However, non-HLA genetic factors are likely to be required for the development of the disease. Among candidate genes is the CTLA-4 (cytotoxic T lymphocyte associated) gene located on chromosome 2q33 in humans, which encodes a cell surface molecule providing a negative signal for T cell activation. AIMS: To investigate CTLA-4 exon 1 polymorphism (position 49 A/G) in patients with coeliac disease. PATIENTS: 101 patients with coeliac disease and 130 healthy controls. METHODS: Allele specific hybridisation and restriction enzyme digestion of polymerase chain reaction amplified genomic DNA. RESULTS: The A allele of the CTLA-4 position 49 polymorphism was found on 82.2% of chromosomes in patients with coeliac disease compared with 65.8% in controls (p < 0.0001), mostly in the homozygous form (68.3% in patients versus 47.7% in controls; odds ratio (OR) 2.36, 95% confidence interval (CI) 1.37 to 4.06, p = 0.002). Four patients only had the G/G genotype compared with 21 controls (OR 0.21, CI 10.07 to 0.64, p = 0.002). These differences were maintained when subjects were stratified according to the HLA class II phenotype, in particular when patients and controls were matched for the presence of the predisposing HLA DQB1*02 (DQ2) allele or HLA-DQA1*0501/DQB1*02 heterodimer. CONCLUSION: The CTLA-4 gene polymorphism is a non-HLA determinant that predisposes to coeliac disease. Whether it directly contributes to disease susceptibility or represents a marker for a locus in linkage disequilibrium with CTLA-4 needs further investigation.  (+info)

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) can regulate dendritic cell-induced activation and cytotoxicity of CD8(+) T cells independently of CD4(+) T cell help. (8/1386)

The mechanisms that regulate the strength and duration of CD8(+) cytotoxic T cell activity determine the effectiveness of an antitumor immune response. To better understand the antitumor effects of anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody treatment, we analyzed the effect of CTLA-4 signaling on CD8(+) T cells in vitro and in vivo. In vitro, cross-linking of CTLA-4 on purified CD8(+) T cells caused decreased proliferative responses to anti-CD3 stimulation and rapid loss of activation marker expression. In vivo, blockade of CTLA-4 by neutralizing anti-CTLA-4 mAb greatly enhanced the accumulation, activation, and cytotoxic activity of CD8(+) T cells induced by immunization with Ag on dendritic cells (DC). This enhanced response did not require the expression of MHC class II molecules on DC or the presence of CD4(+) T cells. These results demonstrate that CTLA-4 blockade is able to directly enhance the proliferation and activation of specific CD8(+) T cells, indicating its potential for tumor immunotherapy even in situations in which CD4(+) T cell help is limited or absent.  (+info)

*CTLA-4

It acts as an "off" switch when bound to CD80 or CD86 on the surface of antigen-presenting cells. The CTLA-4 protein is encoded ... on antigen-presenting cells. CTLA-4 binds CD80 and CD86 with greater affinity and avidity than CD28 thus enabling it to ... needed for firm contact between T cells and antigen-presenting cells (APCs). However, those studies compared CTLA-4 positive ... Antibodies to CTLA-4 may exert additional effects when used in vivo, by binding and thereby depleting regulatory T cells. The ...

*Hashimoto's thyroiditis

CTLA-4 downregulates., i.e. transmits an inhibitory signal to T cells so reduced functioning is associated with increased T- ... "Cytotoxic T-Lymphocyte Associated Antigen 4 Gene Polymorphisms and Autoimmune Thyroid Disease: A Meta-Analysis". Journal of ... Jacobson, Eric M.; Tomer, Yaron (2007). "The CD40, CTLA-4, thyroglobulin, TSH receptor, and PTPN22 gene quintet and its ... Hashimoto's thyroiditis is associated with CTLA-4 (Cytotoxic T-lymphocyte Antigen-4) gene polymorphisms. ...

*TXK (gene)

... phosphorylates the YVKM motif and regulates PI 3-kinase binding to T-cell antigen CTLA-4". Biochem. Biophys. Res. Commun. 252 ( ... 4 (2): 147-51. doi:10.3121/cmr.4.2.147. PMC 1483892 . PMID 16809408. Ohta Y, Haire RN, Amemiya CT, et al. (1996). "Human Txk: ... 12 (4): 937-42. PMID 8632917. Wardenburg JB, Fu C, Jackman JK, et al. (1996). "Phosphorylation of SLP-76 by the ZAP-70 protein- ... 271 (33): 19641-4. doi:10.1074/jbc.271.33.19641. PMID 8702662. Raab M, da Silva AJ, Findell PR, Rudd CE (1997). "Regulation of ...

*LILRB1

Hirohashi N, Nakao M, Kubo K, Yamada A, Shichijo S, Hara A, Sagawa K, Itoh K (Dec 1993). "A novel antigen (H47 Ag) on human ... CTLA-4) on cytokine production by antigen-stimulated human T cells". Journal of Immunology. 168 (1): 207-15. doi:10.4049/ ... The receptor is expressed on immune cells where it binds to MHC class I molecules on antigen-presenting cells and transduces a ... 3.0.CO;2-4. PMID 9933109. Chapman TL, Heikeman AP, Bjorkman PJ (Nov 1999). "The inhibitory receptor LIR-1 uses a common binding ...

*Ipilimumab

... was conceived by Allison and Krummel along with CTLA-4's inhibitory role in T cell activation. They were able to demonstrate ... These antigens are recognized by dendritic cells that present the antigens to cytotoxic T lymphocytes (CTLs) in the lymph nodes ... The CTLs recognize the cancer cells by those antigens and destroy them. However, along with the antigens, the dendritic cells ... T cells to target a greater variety of antigens rather than by increasing the number attacking a single antigen. During "cancer ...

*Immune tolerance

... with B7 on T cells Downregulation of CD80/CD86 costimultory molecules on antigen presenting cells upon interaction with CTLA-4 ... tumor antigens, alloantigens, and self-antigens in inflamed tissue. Immune recognition of non-self-antigens typically ... Self-antigens are present due to endogenous expression, importation of antigen from peripheral sites via circulating blood, and ... Upon exposure to a foreign antigen, either the antigen is eliminated by the standard immune response (resistance), or the ...

*Tumor antigens recognized by T lymphocytes

Genetic basis for clinical response to CTLA-4 blockade in melanoma ". The New England Journal of Medicine. 371(23): 2189-2199. ... In some patients, the majority of the tumor-specific T cells recognize mutated antigens. The contribution of these antigens to ... The carcinoma cells still harbour the viral genes and antigens. As expected T cell responses against antigens encoded by genes ... Cancer therapy targeted at tumor antigens can involve the direct use of these antigens in vaccines, but also the adoptive ...

*Tremelimumab

... blocks the binding of the antigen-presenting cell ligands B7.1 and B7.2 to CTLA-4, resulting in inhibition of B7- ... Mechanism of Pathway: CTLA-4 Inhibition Antoni Ribas (28 June 2012). "Tumor immunotherapy directed at PD-1". New England ... Tremelimumab binds to the protein CTLA-4, which is expressed on the surface of activated T lymphocytes and inhibits the killing ... Unlike Ipilimumab (another fully human anti-CTLA-4 monoclonal antibody), which is an IgG1 isotype, tremelimumab is an IgG2 ...

*Immunologic checkpoint

Examples of such a molecule are cytotoxic T-lymphocyte antigen 4 (CTLA-4 or CD152), which is an inhibitory receptor found on ... particularly against T cells that are specific for tumor antigens. Therefore, the strategy in using immunological checkpoints ...

*T helper 3 cell

Th3 cells are involved in mucosal immunity and protecting mucosal surfaces in the gut from non-pathogenic non-self antigens. ... CTLA-4), which is constitutively expressed on naturally arising Treg cells, it is possible that TGF-β production from Treg ... Additionally, since TGF-β production was induced by cytotoxic T-lymphocyte antigen 4 ( ... cells through CTLA-4-mediated signaling may stimulate the differentiation of both induced Treg cells and Th3 cells. Sakaguchi, ...

*James L. Gulley

The understanding of cytotoxic T-lymphocyte antigen-4 (CTLA-4) which lead to the development of Ipi shows again that Gulley and ... 2008). "Safety and Immunologic Response of a Viral Vaccine to Prostate-Specific Antigen in Combination with Radiation Therapy ... 12 (4): 1260-9. doi:10.1158/1078-0432.CCR-05-2059. PMC 1526707 . PMID 16489082. Arlen, Philip M.; Gulley, James L.; Todd, ... 17 (4): 896-906. doi:10.1158/1078-0432.CCR-10-2463. PMC 3041838 . PMID 21106722. Hoos, Axel; Ibrahim, Ramy; Korman, Alan; ...

*Christopher E. Rudd

By showing that CTLA-4 activates T-cell motility and migration, he has proposed the 'reverse-stop signal model' to account for ... 1989) The CD4 and CD8 antigens are coupled to a protein-tyrosine kinase (p56lck) that phosphorylates the CD3 complex. Proc. ... 2006) Reversal of the TCR stop signal by CTLA-4. Science. 313,1972-5. Wei B, Han L, Abbink TEM, Elisabetta G, Lim D, Thaker R, ... Rudd has also elucidated the signaling mechanisms by which co-receptors CD28, CTLA-4 and ICOS1 modulate T-cell responses. ...

*Fascin

This suggests Treg-mediated suppression of antigen presenting cells is a multi-step process. In addition to CTLA-4 CD80/CD86 ... T regulatory cell adhesion to antigen presenting dendritic cell causes sequestration of Fascin-1, an actin-bundling protein ... 20 (4): 339-45. doi:10.1016/j.cub.2009.12.035. PMC 3163294 . PMID 20137952. Chen, Jiahuan; Ganguly, Anutosh; Mucsi, Ashley D.; ... 15 (4): 1376-1383. doi:10.1158/1078-0432.CCR-08-1789. ISSN 1078-0432. PMID 19228738. Jayo A, Parsons M (October 2010). "Fascin ...

*B7 (protein)

CD28 and CTLA-4 each interact with both B7-1 and B7-2. There are several steps to activation of the immune system against a ... This is also called "Signal 1" and its main purpose is to guarantee antigen specificity of the T cell activation. However, MHC ... Binding of the B7 of APC to CTLA-4 of T-cells causes inhibition of the activity of T-cells. There are two major types of B7 ... CTLA-4-knockout mice are unable to stop immune responses, and develop a fatal massive lymphocyte proliferation. Apart from B7-1 ...

*LAG3

... antigen-specific) Treg suppressive activity. Combination therapies are also ongoing involving LAG-3 antibodies and CTLA-4 or PD ... A new ligand for human leukocyte antigen class II antigens". The Journal of Experimental Medicine. 176 (2): 327-37. doi:10.1084 ... A new ligand for human leukocyte antigen class II antigens". The Journal of Experimental Medicine. 176 (2): 327-37. doi:10.1084 ... An initial characterization of the LAG-3 protein was reported in 1992 showing that it was a ligand for MHC class II antigens ...

*Abatacept

In order for T cells to be activated and attack an antigen, that antigen must be presented to the T cell by an antigen- ... Abatacept consists of a fusion protein of the extracellular domain of CTLA-4 and human IgG1, binds to the B7 protein on the APC ... Abatacept prevents antigen-presenting cells (APCs) from delivering the co-stimulatory signal. This prevents the T cells from ... "ABATACEPT & BELATACEPT: the CTLA-4-Igs". Healthvalue.net. Retrieved 2007-05-25. Dall'Era M, Davis J (2004). "CTLA4Ig: a novel ...

*Death receptor 3

TNFRSF25 is activated by a monogamous ligand, known as TL1A (TNFSF15), which is rapidly upregulated in antigen presenting cells ... effects as costimulatory blockade targeting molecules such as CTLA-4 and PD-1. GRCh38: Ensembl release 89: ENSG00000215788 - ... Similarly, because TNFRSF25 activation is antigen dependent, costimulation of TNFRSF25 together with an autoantigen or with a ... This receptor is expressed preferentially by activated and antigen-experienced T lymphocytes. TNFRSF25 is also highly expressed ...

*CD86

Cluster of Differentiation 86 (also known as CD86 and B7-2) is a protein expressed on antigen-presenting cells that provides ... Chang TT, Kuchroo VK, Sharpe AH (2002). "Role of the B7-CD28/CTLA-4 pathway in autoimmune disease". Current Directions in ... Cluster of differentiation CD80 CD28 CTLA-4 List of human clusters of differentiation for a list of CD molecules GRCh38: ... and CTLA-4 (for attenuation of regulation and cellular disassociation). CD86 works in tandem with CD80 to prime T cells. The ...

*Adenosine A2A receptor

Finally, inhibition of A2AR, either through pharmacologic or genetic targeting, in chimeric antigen receptor (CAR) T-cells ... as shown by an increase in response with blockade to PD-1 and CTLA-4 via monoclonal antibodies as compared to the blockade of a ... especially with the therapeutic success of the blockade of other checkpoint pathways such as PD-1 and CTLA-4. GRCh38: Ensembl ... CTLA-4) receptors, namely to suppress immunologic response and prevent associated tissue damage. Extracellular adenosine ...

*Outline of immunology

Antigen Antigenicity Immunogen Superantigen Allergen Hapten Epitope Linear Conformational Mimotope Tumor antigen Antigen- ... expressed by T Cells CTLA-4 (CD152) PD-1 (CD279) Immune disorder Type 1 hypersensitivity / Allergy / Atopy Foreign (Allergen) ... T cells Antigen receptor - T cell receptor (TCR) Subunits - [email protected] / [email protected] / [email protected] / [email protected] Co-receptors CD8 (CD8α / CD8β) CD4 ... B cells Antigen receptor - B cell receptor (BCR) Subunits- Immunoglobulin heavy chain / Immunoglobulin light chain Co-receptors ...

*Immunotransplant

A number of approaches have been considered to amplify T cell mediated immune responses(e.g. IL-2, CTLA-4, IL-7, CD137), and ... tumor-associated antigens, or whole tumor cells, can induce specific T-cell mediated immune responses. ... Blood 2008;111(4):2112-21. Rapoport AP, Stadtmauer EA, Aqui N, et al. Restoration of immunity in lymphopenic individuals with ... Int J Cancer 2001;94(4):531-9. Rousseau RF, Biagi E, Dutour A, et al. Immunotherapy of high-risk acute leukemia with a ...

*T cell

Antigen-naïve T cells expand and differentiate into memory and effector T cells after they encounter their cognate antigen ... CTLA-4 expression is also up-regulated on activated T cells, which in turn outcompetes CD28 for binding to the B7 proteins. ... These self-antigens are expressed by thymic cortical epithelial cells on MHC molecules on the surface of cortical epithelial ... The second signal licenses the T cell to respond to an antigen. Without it, the T cell becomes anergic, and it becomes more ...

*Cancer immunotherapy

Dendritic cells are antigen presenting cells (APCs) in the mammalian immune system. In cancer treatment they aid cancer antigen ... Using a mouse model of bladder cancer, researchers have found that a local injection of a low dose anti-CTLA-4 in the tumour ... Cancer vaccine Antigen 5T4 Chimeric antigen receptor Coley's Toxins Combinatorial ablation and immunotherapy Cryoimmunotherapy ... Antigens can be added to the antibody and can induce the dendritic cells to mature and provide immunity to the tumor. Dendritic ...

*Type 1 regulatory T cells (Tr1 cells)

Tr1 cells regulate tolerance towards antigens of any origin. Tr1 cells are self or non-self antigen specific and their key role ... Type 1 regulatory T cells poses inhibitory receptor CTLA-4 through which they exert suppressor function. Metabolic disruption: ... and enhances the antigen-specific T-cell response which is necessary for Tr1 cells antigen specifity. CD49b belongs to the ... IL-10 indirectly downregulates MHC II molecules and co-stimulatory molecules on antigen-presenting cells (APC) and force them ...

*Timeline of immunology

Antigen-Antibody binding hypothesis (John Marrack) 1940 - Identification of the Rh antigens (Karl Landsteiner and Alexander ... 2016 - Halpert and Konduri first characterize the role of dendritic cell CTLA-4 in Th-1 immunity 2016 - A third class of immune ... Heat-stable antigen(hi) splenic B cells are an immature developmental intermediate in the production of long-lived marrow- ... 2010 - First immune checkpoint inhibitor, ipilimumab (anti-CTLA-4), is approved by the FDA for treatment of stage IV melanoma ...

*Epithelioid sarcoma

Two of these inhibitory proteins that have been studied recently are CTLA-4 and PD1, and drugs targeting these proteins are in ... Adoptive immunotherapy seeks to expand a population of the body's T-cells that will recognize a specific tumor antigen. T-cells ... They can also include the administration of laboratory-produced antibodies specific to tumor antigens to create or boost an ... Vaccines can deliver various tumor-associated factors (tumor antigens) to the immune system, resulting in a natural antibody ...
The blockade of immune checkpoints, such as programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), is a promising novel approach in cancer treatment. As these pathways are non-redundant, dual targeting may have additive or synergistic antitumour activity. Durvalumab (MEDI4736) is a selective, high affinity human IgG1 mAb that blocks programmed cell death ligand-1 (PD-L1) binding to PD-1 (IC50 0.1 nM) and CD80 (IC50 0.04 nM), and tremelimumab is a selective human IgG2 mAb inhibitor of CTLA-4. In a Phase 1b study (NCT02000947), durvalumab + tremelimumab has shown encouraging clinical activity (objective response rate [ORR] 33% [95% CI 17-54%] across tremelimumab 1 mg/kg cohorts [n = 27]) and manageable tolerability in patients (pts) with both PD-L1-positive and -negative NSCLC. NEPTUNE is a Phase 3 study to determine the efficacy and safety of durvalumab + tremelimumab combination therapy versus standard of care (SoC) platinum-based doublets in the first-line ...
Cancer immunotherapy relies on the ability of the immune system to target tumor specific antigens to generate an immune response. This initial response requires both binding of the MHC/antigen peptide to T-cell receptor complex along with a second co-stimulatory signal created by the binding of CD28 on the T cell with B7 located on the antigen presenting cell. Regulatory checkpoints, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), serve to attenuate this signal, thereby preventing autoimmunity. Its key role in regulating the immune system has made CTLA-4 an attractive therapeutic target for cancer, with the development of fully human monoclonal antibodies that have successfully targeted CTLA-4 in clinical trials. Augmentation of the immune response via blockade of CTLA-4 represents a significant advance in the field of oncology and has demonstrated an improvement in survival for patients with metastatic melanoma. An increased understanding of the components of this pathway and the ...
Immune checkpoint inhibitors (ICIs), including antibodies targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein-1 (PD-1), have shown durable treatment...
Background: Associations between polymorphisms in cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) / interleukin-18 (IL-18) and susceptibility to liver diseases were already reported by many publications. The aim of this meta-analysis was to clarify associations between polymorphisms in CTLA-4/IL-18 and liver diseases by combing the results of all relevant publications. Methods: Eligible publications were searched from Pubmed, Embase, WOS and CNKI. The latest literature searching update was performed on 2nd October, 2019. We used Review Manager to combine the results of individual studies. Results: Sixty-seven studies were included in this study. Combined results revealed that CTLA-4 rs231775 (dominant comparison: OR 0.83, 95 % CI 0.79-0.88; recessive comparison: OR 1.33, 95 % CI 1.23-1.43; allele comparison: OR 0.84, 95 % CI 0.78-0.90), IL-18 rs1946518 (dominant comparison: OR 0.85, 95 % CI 0.78-0.92; recessive comparison: OR 1.29, 95 % CI 1.13-1.48; allele comparison: OR 0.79, 95 % CI ...
The emergence of immune checkpoint inhibitors for solid tumor treatments represents a major oncological advance. Since the approval of ipilimumab, a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody, for the treatment of metastatic melanoma, many drugs, especially those targeting PD1/PD-L1, have demonstrated promising antitumor effects in many types of cancer. By reactivating the immune system (IS), these immunotherapies have led to the development of new toxicity profiles, also called immune-related adverse events (irAEs). IrAEs can involve many organ systems, and their management is radically different from that of cytotoxic drugs; irAEs require immunosuppressive treatments, such as corticoids or tumor necrosis factor alpha (TNFα) antibody. Additionally, the occurrence of irAEs has raised significant questions. Here, we summarize progress that has been made toward answering these questions, focusing on 1) the impact of immunotherapy dose on irAE occurrence, 2) the correlation ...
... therapies have attracted amounts of attention from scientists who are devoted to cancer treatment. What is immune checkpoint? It is a kind of co-stimulatory and inhibitory signal for regulating the antigen recognition of T cell receptor (TCR) in the process of immune responce. When immune system is attacking pathogens, these immune checkpoint molecules can protect the normal tissues from damage. The cancer cells cleverly escape from immune attack by dysregulating immune checkpoint related proteins. Immune checkpoint therapy relys on functioning immune system with agonists of co-stimulatory signals or antagonists of inhibitory signals. Over these years there are two immune checkpoint receptors that have been actively studied: cytotoxic T‑lymphocyte-associated antigen 4 (CTLA-4 / CD152) and programmed cell death protein 1 (PD1 / PDCD1 / CD279). The corresponding antibodies can inhibit the functioning of the receptors and enhance antitumour immunity. Furthermore, multiple ...
This medicine is human anti-CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4) monoclonal antibody. It binds to CTLA-4 receptor of T-cell (immune cell) to enhance growth/activation/cytotoxic activity of tumor antigen-specific T-cell. It consequently suppresses tumor growth. It also decreases regulatory T-cell (Treg) function and reduces the number of Treg in the tumor tissue. It consequently increases anti-tumor immune response and suppresses tumor growth ...
Background: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects. Objective: We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. Methods: Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. Results: We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%;median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16%(n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal ...
The combined results show that the efficacy of therapeutic vaccination against experimental melanoma is markedly increased by interfering with mechanisms that normally keep autoimmune responses in check. Antitumor treatment is strongly improved if vaccination is either accompanied by CTLA-4 blockade or preceded by a depletion of CD25+ Treg cells. These intervention strategies act synergistically, in that combination of CTLA-4 blockade and depletion of CD25+ Treg cells results in maximal efficacy of therapeutic vaccination. The potency of the different treatment modalities for preventing B16 melanoma outgrowth strongly correlates with the extent of autoimmune skin depigmentation in the treated mice as well as with the frequency of TRP-2180-188-specific CTLs detected in the periphery. Furthermore, antitumor protection was abrogated upon depletion of the CD8+ T cell subset. Therefore, our data indicate that the CTL response against melanoma-associated autoantigens is an important component of the ...
Our findings support the hypothesis that T cell activation is a critical and proximal event in the complex chronic inflammatory cascade that culminates in the generation of psoriatic plaques. To our knowledge, this is the first report documenting the accumulation of mature DCs in a human autoimmune target organ, the skin. Additionally, the resolution of activated phenotypes on lesional keratinocytes, DCs, and vascular endothelium after T cell costimulatory blockade has not previously been reported. Thus, these data expand upon our prior observations (15) and provide possible mechanisms for the observed durable reduction in intralesional T cells after administration of CTLA4Ig. We have demonstrated that a reduced capacity for lesional T cell clonal expansion (due to reversion of the lesional skin APC population to a less mature/immunocompetent state) and decreased vascular recruitment may both have been contributory factors. These observations suggest that clinical activity in this chronic ...
Within the paradigm of the two-signal model of lymphocyte activation, the interest in costimulation has witnessed a remarkable emergence in the past few years with the discovery of a large array of molecules that can serve this role, including some with an inhibitory function. Interest has been further enhanced by the realization of these molecules potential as targets to modulate clinical immune responses. Although the therapeutic translation of mechanistic knowledge in costimulatory molecules has been relatively straightforward, the capacity to target their inhibitory counterparts has remained limited. This limited capacity is particularly apparent in the case of the cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), a major negative regulator of T cell responses. Because there have been several previous comprehensive reviews on the function of this molecule, we focus here on the physiological implications of its structural features. Such an exercise may ultimately help us to design
Immune checkpoint inhibitors are becoming a cornerstone of cancer immunotherapy as a result of their clinical success in relieving immune suppression and driving durable antitumor T cell responses in certain subsets of patients. Unfortunately, checkpoint inhibition is also associated with treatment-related toxicities that result in a myriad of side effects, ranging from mild and manageable to severe and debilitating. In this issue of the JCI, Das and colleagues report an association between early therapy-induced changes in circulating B cells and an increased risk of high-grade immune-related adverse events (IRAEs) in patients treated with checkpoint inhibitors that target cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and programmed cell death protein 1 (PD1). These findings identify potential predictive biomarkers for high-grade IRAEs that may be leveraged to improve patient monitoring and may prompt new treatment strategies to prevent IRAEs.. ...
Immune checkpoint inhibitors are becoming a cornerstone of cancer immunotherapy as a result of their clinical success in relieving immune suppression and driving durable antitumor T cell responses in certain subsets of patients. Unfortunately, checkpoint inhibition is also associated with treatment-related toxicities that result in a myriad of side effects, ranging from mild and manageable to severe and debilitating. In this issue of the JCI, Das and colleagues report an association between early therapy-induced changes in circulating B cells and an increased risk of high-grade immune-related adverse events (IRAEs) in patients treated with checkpoint inhibitors that target cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and programmed cell death protein 1 (PD1). These findings identify potential predictive biomarkers for high-grade IRAEs that may be leveraged to improve patient monitoring and may prompt new treatment strategies to prevent IRAEs.. ...
Immune checkpoint inhibitors are becoming a cornerstone of cancer immunotherapy as a result of their clinical success in relieving immune suppression and driving durable antitumor T cell responses in certain subsets of patients. Unfortunately, checkpoint inhibition is also associated with treatment-related toxicities that result in a myriad of side effects, ranging from mild and manageable to severe and debilitating. In this issue of the JCI, Das and colleagues report an association between early therapy-induced changes in circulating B cells and an increased risk of high-grade immune-related adverse events (IRAEs) in patients treated with checkpoint inhibitors that target cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and programmed cell death protein 1 (PD1). These findings identify potential predictive biomarkers for high-grade IRAEs that may be leveraged to improve patient monitoring and may prompt new treatment strategies to prevent IRAEs.. ...
Immune checkpoint inhibitors are becoming a cornerstone of cancer immunotherapy as a result of their clinical success in relieving immune suppression and driving durable antitumor T cell responses in certain subsets of patients. Unfortunately, checkpoint inhibition is also associated with treatment-related toxicities that result in a myriad of side effects, ranging from mild and manageable to severe and debilitating. In this issue of the JCI, Das and colleagues report an association between early therapy-induced changes in circulating B cells and an increased risk of high-grade immune-related adverse events (IRAEs) in patients treated with checkpoint inhibitors that target cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and programmed cell death protein 1 (PD1). These findings identify potential predictive biomarkers for high-grade IRAEs that may be leveraged to improve patient monitoring and may prompt new treatment strategies to prevent IRAEs.. ...
Immune checkpoint inhibitors are becoming a cornerstone of cancer immunotherapy as a result of their clinical success in relieving immune suppression and driving durable antitumor T cell responses in certain subsets of patients. Unfortunately, checkpoint inhibition is also associated with treatment-related toxicities that result in a myriad of side effects, ranging from mild and manageable to severe and debilitating. In this issue of the JCI, Das and colleagues report an association between early therapy-induced changes in circulating B cells and an increased risk of high-grade immune-related adverse events (IRAEs) in patients treated with checkpoint inhibitors that target cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and programmed cell death protein 1 (PD1). These findings identify potential predictive biomarkers for high-grade IRAEs that may be leveraged to improve patient monitoring and may prompt new treatment strategies to prevent IRAEs.. ...
Immune checkpoint inhibitors are becoming a cornerstone of cancer immunotherapy as a result of their clinical success in relieving immune suppression and driving durable antitumor T cell responses in certain subsets of patients. Unfortunately, checkpoint inhibition is also associated with treatment-related toxicities that result in a myriad of side effects, ranging from mild and manageable to severe and debilitating. In this issue of the JCI, Das and colleagues report an association between early therapy-induced changes in circulating B cells and an increased risk of high-grade immune-related adverse events (IRAEs) in patients treated with checkpoint inhibitors that target cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and programmed cell death protein 1 (PD1). These findings identify potential predictive biomarkers for high-grade IRAEs that may be leveraged to improve patient monitoring and may prompt new treatment strategies to prevent IRAEs.. ...
Immune checkpoint inhibitors are becoming a cornerstone of cancer immunotherapy as a result of their clinical success in relieving immune suppression and driving durable antitumor T cell responses in certain subsets of patients. Unfortunately, checkpoint inhibition is also associated with treatment-related toxicities that result in a myriad of side effects, ranging from mild and manageable to severe and debilitating. In this issue of the JCI, Das and colleagues report an association between early therapy-induced changes in circulating B cells and an increased risk of high-grade immune-related adverse events (IRAEs) in patients treated with checkpoint inhibitors that target cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and programmed cell death protein 1 (PD1). These findings identify potential predictive biomarkers for high-grade IRAEs that may be leveraged to improve patient monitoring and may prompt new treatment strategies to prevent IRAEs.. ...
Immune checkpoint inhibitors are becoming a cornerstone of cancer immunotherapy as a result of their clinical success in relieving immune suppression and driving durable antitumor T cell responses in certain subsets of patients. Unfortunately, checkpoint inhibition is also associated with treatment-related toxicities that result in a myriad of side effects, ranging from mild and manageable to severe and debilitating. In this issue of the JCI, Das and colleagues report an association between early therapy-induced changes in circulating B cells and an increased risk of high-grade immune-related adverse events (IRAEs) in patients treated with checkpoint inhibitors that target cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and programmed cell death protein 1 (PD1). These findings identify potential predictive biomarkers for high-grade IRAEs that may be leveraged to improve patient monitoring and may prompt new treatment strategies to prevent IRAEs.. ...
Immune checkpoint inhibitors are becoming a cornerstone of cancer immunotherapy as a result of their clinical success in relieving immune suppression and driving durable antitumor T cell responses in certain subsets of patients. Unfortunately, checkpoint inhibition is also associated with treatment-related toxicities that result in a myriad of side effects, ranging from mild and manageable to severe and debilitating. In this issue of the JCI, Das and colleagues report an association between early therapy-induced changes in circulating B cells and an increased risk of high-grade immune-related adverse events (IRAEs) in patients treated with checkpoint inhibitors that target cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and programmed cell death protein 1 (PD1). These findings identify potential predictive biomarkers for high-grade IRAEs that may be leveraged to improve patient monitoring and may prompt new treatment strategies to prevent IRAEs.. ...
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PRIMARY OBJECTIVES:. I. Determine the maximum tolerated dose of anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-010) (ipilimumab) administered with sargramostim (GM-CSF) in patients with metastatic androgen-independent prostate cancer. (Phase I) II. Determine the safety of this regimen in these patients. (Phase I) III. Evaluate the efficacy as measured by reduction in PSA associated with combining GM-CSF with CTLA-4 blockade with ipilimumab at a dosage of 3 mg/kg given monthly x 6 doses (d1 of courses 1-6). (Cohort Expansion). SECONDARY OBJECTIVES:. I. Determine the T-cell immunity and T-cell response in patients treated with this regimen. (Phase I) II. Determine the pharmacokinetics of MDX-010 in these patients. (Phase I) III. Determine the prostate-specific antigen and/or objective responses in patients treated with this regimen. (Phase I) IV. Determine the percentages of activated, naive, and memory T-cells. (Cohort Expansion) V. Determine the measurement of T-cell ...
PRIMARY OBJECTIVES:. I. Determine the maximum tolerated dose of anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-010) (ipilimumab) administered with sargramostim (GM-CSF) in patients with metastatic androgen-independent prostate cancer. (Phase I) II. Determine the safety of this regimen in these patients. (Phase I) III. Evaluate the efficacy as measured by reduction in PSA associated with combining GM-CSF with CTLA-4 blockade with ipilimumab at a dosage of 3 mg/kg given monthly x 6 doses (d1 of courses 1-6). (Cohort Expansion). SECONDARY OBJECTIVES:. I. Determine the T-cell immunity and T-cell response in patients treated with this regimen. (Phase I) II. Determine the pharmacokinetics of MDX-010 in these patients. (Phase I) III. Determine the prostate-specific antigen and/or objective responses in patients treated with this regimen. (Phase I) IV. Determine the percentages of activated, naive, and memory T-cells. (Cohort Expansion) V. Determine the measurement of T-cell ...
In this study, we show that bispecific tandem ScFv against human CTLA-4 can have an unexpected biological effect by revealing the plasticity for signaling through the cytoplasmic domain of this surface receptor. On one hand, when CTLA-4 binds B7.1 or B7.2 in the context of coligation with the TCR, it transduces a signal that inhibits T cell activation (reviewed in Refs. 1 , 2 , and 4, 5, 6). On the other hand, we show in this study that binding of a bispecific tandem ScFv ligand of CTLA-4 causes the same cytoplasmic domain to transduce a signal that, by itself, activates the T cell without the need for coligation of the TCR. Although triggered by different ligands that bind to different sites on CTLA-4, both responses involve PP2A. The inhibitory function of CTLA-4 correlates with a decrease in its association with PP2A (19), while the activating function of CTLA-4 correlates with an increase in its association with PP2A.. Activation of T cells by 24:26 is not the result of functional blockade ...
CTLA-4 (Cytotoxic T-lymphocyte-associated protein 4, CD152) protein. CTLA4 blocking antibodies are used in cancer therapy (immune checkpoint blockade therapy). Space-filling model with conventional colour coding. - Stock Image F019/2238
A soluble fusion protein consisting of the extracellular domain of human cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1 (IgG1) with immunosuppressive activity. Abatacept binds CD80 and CD86 on antigen presenting cells (APCs), blocking interaction with CD28 on T lymphocytes, which initiates a co-stimulatory signal required for full activation of T lymphocytes.
Novus Biologicals Human CTLA-4 ELISA Kit 96 Tests Electrophoresis, Western Blotting and ELISA:ELISA Reagents, Plates and Accessories:ELISA Kits:C-E ELISA Kits
Our results support the concept that variants in CTLA4 provide the basis for a novel Mendelian form of early-onset CD associated with systemic autoimmunity. Incomplete penetrance of autoimmunity further indicates the presence of other genetic and/or environmental modifiers.A novel missense variant was identified in CTLA4 encoding CTLA-4, a coinhibitory protein expressed by T cells and required for regulation of T cell activation. The residue affected by the mutation, CTLA-4 Tyr60, is evolutionarily highly conserved, and the identified Y60C variant is predicted to affect protein folding and structural stability and demonstrated to cause impaired CTLA-4 dimerisation and CD80 binding. Intestinal inflammation and autoimmunity in carriers of CTLA-4 Y60C exhibit incomplete penetrance with a spectrum of clinical presentations ranging from asymptomatic carrier status to fatal autoimmunity and intestinal inflammation. In a clinically affected CTLA-4 Y60C carrier, T cell proliferation was increased in ...
Tremelimumab (formerly ticilimumab, CP-675,206) is a fully human monoclonal antibody against CTLA-4. It is an immune checkpoint blocker. Previously in development by Pfizer, it is now in investigation by MedImmune, a wholly owned subsidiary of AstraZeneca. It has been undergoing human trials for the treatment of various cancers but has not attained approval for any. Tremelimumab aims to stimulate an immune system attack on tumors. Cytotoxic T lymphocytes (CTLs) can recognize and destroy cancer cells. However, there is also an inhibitory mechanism (immune checkpoint) that interrupts this destruction. Tremelimumab turns off this inhibitory mechanism and allows CTLs to continue to destroy the cancer cells. This is immune checkpoint blockade. Tremelimumab binds to the protein CTLA-4, which is expressed on the surface of activated T lymphocytes and inhibits the killing of cancer cells. Tremelimumab blocks the binding of the antigen-presenting cell ligands B7.1 and B7.2 to CTLA-4, resulting in ...
Programmed cell death protein 1/programmed cell death protein ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte antigen 4/B7 (CTLA-4/B7) pathways are key regulators in T-cell activation and tolerance. Nivolumab, pembrolizumab (PD-1 inhibitors), atezolizumab (PD-L1 inhibitor) and ipilimumab (CTLA-4 inhibitor) are monoclonal antibodies approved for treatment of several advanced cancers. Immune checkpoint inhibitors (ICIs)-related hypophysitis is described more frequently in patients treated with anti-CTLA-4; however, recent studies reported an increasing prevalence of anti-PD-1/PD-L1-induced hypophysitis which also exhibits slightly different clinical features. We report our experience on hypophysitis induced by anti-PD-1/anti-PD-L1 treatment. We present four cases, diagnosed in the past 12 months, of hypophysitis occurring in two patients receiving anti-PD-1, in one patient receiving anti-PD-1 and anti-CTLA-4 combined therapy and in one patient receiving anti-PD-L1. In this case series, timing, ...
A high mutational load and the presence of a T-cell-"inflamed" environment may independently predict for treatment response to pembrolizumab (Keytruda) and progression-free survival, according to a study presented by Tanguy Seiwert, MD, of the University of Chicago, at the 2017 ASCO-SITC Clinical Immuno-Oncology Symposium.1. "Nonsynonymous mutational load and neoantigen load as well as an 18-gene immune-related gene-expression profiling were significantly associated with overall response and progression-free survival to pembrolizumab across multiple indications," Dr. Seiwert revealed. "This suggests that tumor antigenicity and T-cell infiltration may provide complementary information for expected pembrolizumab activity" and may be useful in characterizing responses to immunotherapies, he said.. Tumor mutational load has been shown to correlate with benefit from drugs blocking cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) in multiple tumor types. ...
Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)--which encodes a vital negative regulatory molecule of the immune system--as candidates for primary determinants of risk of the common autoimmune disorders Graves disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1 kb 3 region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified
The administration of anti-CTLA-4 Ab to patients with metastatic melanoma induced durable objective clinical responses that were highly associated with the induction of autoimmune side effects (23, 24). However, the mechanism responsible for tumor regression and autoimmunity was unclear, although two dominant hypotheses have been proposed. CTLA-4 is constitutively expressed on CD4+CD25+ T regulatory cells (25, 26); hence, the administration of an anti-CTLA-4 Ab may lead to the depletion or inhibition of these regulatory cells, with a resultant increase in the activity of effector T cells. Alternatively, CTLA-4 engagement imparts an inhibitory signal to the T cell (5), and the blockade of CTLA-4 may directly tip the balance toward T cell effector function. These two possibilities have been studied in this report.. We first addressed the impact of anti-CTLA-4 Ab on CD4+CD25+ T cell regulatory cell function in vitro using a coculture suppression assay. This proliferation assay was developed to ...
We studied the association of cytotoxic T lymphocyte antigen-4 gene (CTLA4) polymorphisms with the development of type 1 diabetes (T1D) in Korean children and adolescents. A total of 176 Korean subjects (92 females and 84 males) with childhood-onset T1D were studied. The A/G polymorphism at position 49 in CTLA4 exon 1 and the C/T polymorphism at position -318 in the CTLA4 promoter were analyzed by PCR-RFLP methods. The genotype and allele frequencies of the CTLA4 polymorphisms in the T1D patients were not different from those in the controls. These polymorphisms were not associated with the clinical characteristics or the development of autoimmune thyroid disease in the T1D patients. The frequency of the A allele was significantly higher in the patients that did not have two out of the three susceptible HLA-DRB1 alleles, which were DRB1*0301, *0405 and *09012, compared to the controls (P,0.05). These results suggest that CTLA4 polymorphisms do not directly confer any susceptibility to T1D. ...
Costimulation is a fundamental principle of T-cell activation. In addition to T-cell receptor engagement, the interaction between CD80 and/or CD86 with CD28 and/or cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptors is required to regulate T-cell activation and tolerance. While the importance of costimulation is clearly established, the exact molecular mechanism is unknown. We demonstrate that T-cell proliferation and the ability of CD8(+) T-effector cells to kill were enhanced slightly by CD80 but dramatically by CD86 costimulation. To further analyse the cellular process of costimulation, we developed a single-cell assay to analyse Ca(2+) signals following costimulation with bi-specific antibodies. We found that this stimulation method worked in every human T-cell that was analysed, making it one of the most efficient T-cell activation methods to date for primary human T cells. The enhanced proliferation and killing by costimulation was paralleled by an increase of Ca(2+) influx following CD86 ...
Antibody-based targeting of the immune suppressor molecule cytotoxic T-lymphocyte antigen 4 (CTLA-4) with ipilimumab has been studied in metastatic melanoma in a number of clinical trials, including a recent phase III trial. This marks the first randomized clinical trial reporting an overall survival benefit using immune modulation in metastatic melanoma. Along with its therapeutic benefits, ipilimumab presents unique challenges to clinicians; these are related to the monitoring of treatment response and the management of drug-related toxicities. This drug is currently being investigated in various cancers, and its indications are likely to be expanded. 1
Expression profiles of CTLA-4 in breast cancer. CTLA-4 was expressed in cytoplasm and cell membrane of interstitial lymphocytes (a); CTLA-4+ cytoplasmic dots we
Some of the most effective immunotherapies target immune checkpoints exploited by cancers to decrease immune activity. For example, activation of T-helper cells upon binding to antigens on the antigen-presenting cell (APC) can be modulated by other receptor-ligand interactions between the 2 cells. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) are 2 examples of receptors on T cells that, upon ligand binding, trigger a signaling cascade that inhibits T-cell activation, limiting the immune response.15-18 Antibodies against these receptors (ipilimumab, nivolumab, pembrolizumab) prevent receptor-ligand interaction, removing the inhibition of T-cell activation and "releasing the brake" on the immune response.19-21. Pembrolizumab: Randomized trials in patients with unresectable stage III or IV metastatic disease have shown that pembrolizumab (monotherapy), like nivolumab, improves response and progression-free survival (PFS) compared with chemotherapy or ...
To endow the immune system with the capacity to fight cancer has always attracted attention, although the clinical results obtained have been until recently disappointing. Cutaneous melanoma is a highly immunogenic tumor; therefore most of the attempts to produce cancer vaccines have been addressed to this disease. New advances in the comprehension of the mechanisms of antigen presentation by dendritic cells, in the immune responses triggered by adjuvants, as well as the understanding of the role of immunosuppressor molecules such as Cytotoxic T-lymphocyte antigen-4 (CTLA-4), which led to the recent approval of the anti-CTLA-4 monoclonal antibody ipilimumab, have opened new hopes about the installment of immunotherapy as a new modality to treat cancer.
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Abstract Download Blockade of various immune targets such as cytotoxic T-lymphocyte antigen-4 and Programmed cell death leads to immune-mediated tumor regression and immune-related adverse events, predominantly gastrointestinal events including diarrhea and colitis. The current review is done to understand the […]. ...
One reason for the poor immunogenicity of many tumors may be that they cannot provide signals for CD28-mediated costimulation necessary to fully activate T cells. It has recently become apparent that CTLA-4, a second counterreceptor for the B7 family of costimulatory molecules, is a negative regulator of T cell activation. Here, in vivo administration of antibodies to CTLA-4 resulted in the rejection of tumors, including preestablished tumors. Furthermore, this rejection resulted in immunity to a secondary exposure to tumor cells. These results suggest that blockade of the inhibitory effects of CTLA-4 can allow for, and potentiate, effective immune responses against tumor cells.. ...
At Sundays Plenary Session, a landmark study provided new data that have implications for changing clinical practice. Steven ODay, MD, of the Angeles Clinic and Research Institute, reported that ipilimumab alone or in combination with vaccine increased overall survival (OS) in patients with unresectable stage III/IV melanoma for whom previous treatment had failed (Abstract 4). "This is an historic first - the first phase III randomized study showing improvement in median and long-term survival in patients with metastatic melanoma," Dr. ODay said. Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte antigen 4 (CTLA-4), is an immune therapy directed against T-cells. The... Continue reading ...
IPILIMUMAB, 1 INDICATIONS AND USAGE YERVOY is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody indicated for: •Treatment of unresectable or metastatic melanoma in adults and pediatric patients
Hereditary Factors:, Linkage:, Origin:, Serology: Antigen, Congenic Resistant Lines: A.SW, Genes: Ly-3 - Lymphocyte antigen-3, Lyt-3, Ly-1 - Lymphocyte antigen-1, ly-a, Lyt-1, mu - greek, Ly-2 - Lymphocyte antigen-2, Lyt-2, Strains: A(CAL-A) (A/J), AKR, BALB/C, CBA/H-T6T6, CE, C3H/AN, C3H/BI, C3HF (C3HB, ZB), C57BL/6, C57BL/10, C57BR/CD, C58, DA, DBA/2 (212), GR, H-2I (HTI), H-2H (HTH), I, L (P), LP, NZB, PL (PLA, PLB), RF (W), SJL, ST/B (STB), SWR, 129. ...
Dr. Allisons pioneer work has transformed the fields of basic and tumour immunology. Early in his career, he identified and characterized key molecules involved in T-cell activation, including the T-cell receptor (TCR), the prototypical costimulatory receptor CD28 and coinhibitory receptor CTLA-4, providing evidence that T-cell responses are determined by a complex process involving antigen driven TCR signalling plus integration of costimulatory and coinhbitory signals. His landmark translation studies showing antibody-mediated blockade of CTLA-4 co-inhibitory function could enhance antitumor immunity and result in tumour rejection in mice prompted clinical development of ipilimumab, a CTLA-4 blocking monoclonal antibody. Ipilimumab is the first drug of its kind to show survival benefit in melanoma patients and was approved by the FDA in 2011 as a standard-of-care therapy for late-stage melanoma patients. Dr. Allisons concept of antibody-mediated blockade of immunologic checkpoints as cancer ...
Antibodies that target immune checkpoint molecules, such as CTLA4, provide robust antitumor effects in a subset of patients. Unfortunately, not all patients respond to immune checkpoint inhibition, and some develop life-threatening immune-related adverse events (irAEs). The mechanisms that underlie irAEs from immune checkpoint inhibition are not fully understood, and treatment strategies are currently limited to targeting inflammatory mediators. In this issue of the JCI, Pai et al. report on their development of a modified CTLA4 antibody that shields the inner CTLA4-binding domain until the antibody is within the protease-rich tumor microenvironment. In a lymphopenic murine model reconstituted with naive CD4+ T cells, adapted anti-CTLA4 reduced the occurrence of irAEs and enhanced antitumor effects. This thought-provoking study lays the groundwork for further exploration of this adapted antibody in immunocompetent hosts and introduction of this adaptation to other immune checkpoint molecules. It ...
11 Feb 2016. by ecancer reporter Janet Fricker. The combination of the PD-1 inhibitor durvalumab and the CTLA-4 inhibitor tremelimumab achieved higher anti tumour activity than either drug alone in non-small cell lung cancer (NSCLC), reports a phase 1b study.. The study, published in Lancet Oncology, showed that toxic effects but not antitumour activity increase with rising doses of tremelimumab, but that there were no differences in toxic effect among different doses of durvalumab when tremelimumab remained constant.. Evidence of anti tumour activity was found irrespective of patient PD-L1 status.. Early clinical trials suggest blockade of multiple immune checkpoints might have greater anti-tumour activity than blockade of one checkpoint in melanoma and NSCLC.. Drugs that block the PD-L1/ PD-1 pathway act in the tumour microenvironment and prevent inhibition of T-cell function; while drugs that block the CTLA4 pathway act in the lymphoid compartment to expand the number and repertoire of ...
T cell activation in response to antigen is increased by the administration of binding agents that block CTLA-4 signaling. When CTLA-4 signaling is thus blocked, the T cell response to antigen is released from inhibition. Such an enhanced response is useful for the treatment of tumors, chronic viral infections, and as an adjuvant during immunization.
Detect and quantitate human CTLA-4 in buffered solution, and cell culture supernatants using a homogeneous AlphaLISA no-wash assay.
The HuGEMM CTLA-4 mouse model is a chimeric tumor model where the mouse immune system is functional and the CTLA-4 receptors have been humanized
The FDA has begun to expand the approved uses of immune checkpoint blockade antibodies targeting CTLA-4 and PD-1. Blocking either checkpoint relieves the negative regulation of T-cells resulting in significant responses in patients with cancer. Data has now begun to emerge regarding differences between these two therapies. While αPD-1 therapy has a greater response rate (~30% vs. 11%) according to RECIST criteria, recent reports have suggested responses to αPD-1 may not be as durable as αCTLA-4. 25% of patients who initially responded to αPD-1 have tumor relapse within 24 months. In contrast, the 3-year survival rate of patients treated with αCTLA-4 is at least ~25% suggesting a durable response. Previous studies in bacterial or chronic LCMV infectious models have shown that αCTLA-4 can increase CD8+ memory T-cell formation, whereas genetic ablation of PD-1 on T-cells often promotes the terminally differentiated exhausted CD8+ T-cell phenotype, while attenuating memory T-cell formation. ...
Explore CTLA-4, CD28, CD80 (B7-1) and CD86 (B7-2) interactions with clones you know and trust for Flow Cytometry. Exceptionally priced, every day!
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Such controversial results as well as the fact that some people bearing G/G genotype of CTLA-4 ... close association with MHC class II alleles [12].
Estimating the kon and koff for sCD80 binding CTLA-4 Ig. (A) Example of primary data. sCD80 (265 nM) was injected (solid bar) at 40 μl/min through FCs with n
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Immune checkpoint pathways - The system of checks and balances in place to prevent overactivation of the immune system. Different pathways function at different stages of the immune response to help regulate the length and intensity of T-cell activity; turning on an immune checkpoint typically results in shutting down the immune system response.. Immunosuppression - A condition in which the immune system is prevented from launching successful attacks to protect the body against infection and disease.. Immunotherapy - A type of cancer treatment that focuses on using the bodys own immune system to fight cancer.. Immune-related adverse events (IRAEs) - Auto- immune reactions that occur as a result of boosting the immune system. Severe reactions may include colitis, dermatitis and hepatitis.. Interferon - A protein released by immune cells that helps regulate different immune cell activity; types of interferon include alpha, beta, gamma and lambda. Different types help regulate different functions, ...
Ipilimumab, a novel therapy for metastatic melanoma, inhibits cytotoxic T-lymphocyte apoptosis, causing both antitumor activity and significant autoimmunity, including autoimmune thyroiditis. Steroids are frequently used in treatment of immune-related adverse events; however, a concern regarding the property of steroids to reduce therapeutic antitumor response exists. This study describes the first reported case of ipilimumab-associated thyroid storm and implicates iopanoic acid as an alternative therapy for immune-mediated adverse effects. An 88-year-old woman with metastatic melanoma presented with fatigue, anorexia, decreased functional status, and intermittent diarrhea for several months, shortly after initiation of ipilimumab - a recombinant human monoclonal antibody to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4). On arrival, she was febrile, tachycardic, and hypertensive with a wide pulse pressure, yet non-toxic appearing. She had diffuse, non-tender thyromegaly. An ...
In a systematic review and meta-analysis reported in JAMA Oncology, Barroso-Sousa et al evaluated the incidence of endocrine dysfunction in patients receiving currently approved immune checkpoint inhibitors for various advanced solid tumors. Patients who received combination therapy were found to have an increased risk of thyroid dysfunction and hypophysitis.. Study Details. A PubMed search through July 2016 identified 38 randomized clinical trials of ipilimumab (Yervoy; cytotoxic T-lymphocyte-associated protein 4 [CTLA-4] inhibitor), nivolumab (Opdivo; programmed cell death protein 1 [PD-1] inhibitor), pembrolizumab (Keytruda; PD-1 inhibitor), and atezolizumab (Tecentriq; programmed cell death protein ligand [PD-L1] inhibitor), involving a total of 7,551 patients. Regimens were categorized into monotherapy with a PD-1 inhibitor, a CTLA-4 inhibitor, or a PD-L1 inhibitor, and combination therapy with a PD-1 plus CTLA-4 inhibitor. Outcomes of interest were the incidence of all-grade ...
The monoclonal antibody UC10-4B9 reacts with CD152, also known as cytotoxic T lymphocyte antigen-4 (CTLA-4), which is a 33 kDa member of the immunoglobin superfamily and is expressed on activated T cells at a low level. CTLA-4 and CD28 have similarities concerning B7 family counter-receptors. While CD28 delivers a costimulary signal in T cell activation, CD152 restricts the progression of T cells to an activated state by inhibiting interleukin 2 (IL-2) secretion and cellular proliferation. A large proportion of CTLA-4 is intracellular localized. For a complete detection it may be necessary to assess intracellular staining in addition to surface expression of CD152. - Liechtenstein
Melanoma is the most malignant form of skin cancer. The five-year survival rate for metastatic melanoma is 19.9%. Although targeted therapy of BRAF and MEK inhibitors were developed for melanoma, resistance to therapy is inevitable. Immune checkpoint blockade, which reverses the suppression of the immune system, on the other hand, has shown a durable response in 20-30% of patients with metastatic melanoma. However, more predictive and robust biomarkers of response to this therapy are still needed, and resistance mechanisms remain incompletely understood. To address this, we examined a cohort of metastatic melanoma patients treated with sequential checkpoint blockade against cytotoxic T lymphocyte antigen-4 (CTLA-4) followed by programmed death receptor-1 (PD-1) by immunogenomic profile analyses from serial tumor biopsies. From immune profiling (12 marker immunohistochemistry and NanoString Gene Expression Profiling), we found that adaptive immune signatures in tumor biopsies obtained from early on
Design of efficacious Treg-based therapies and establishment of clinical tolerance in autoimmune diseases have proven to be challenging. The clinical implementation of Treg immunotherapy has been hampered by various impediments related to the stability and isolation procedures of Tregs as well as the specific in vivo targets of Treg modalities. Herein, we have demonstrated that Foxp3+ Tregs potently suppress autoimmune responses in vivo through inhibition of the autophagic machinery in DCs in a cytotoxic T-lymphocyte-associated protein 4-dependent (CTLA4-dependent) manner. Autophagy-deficient DCs exhibited reduced immunogenic potential and failed to prime autoantigen-specific CD4+ T cells to mediate autoimmunity. Mechanistically, CTLA4 binding promoted activation of the PI3K/Akt/mTOR axis and FoxO1 nuclear exclusion in DCs, leading to decreased transcription of the autophagy component microtubule-associated protein 1 light chain 3β (Lc3b). Human DCs treated with CTLA4-Ig, a fusion protein ...
Design of efficacious Treg-based therapies and establishment of clinical tolerance in autoimmune diseases have proven to be challenging. The clinical implementation of Treg immunotherapy has been hampered by various impediments related to the stability and isolation procedures of Tregs as well as the specific in vivo targets of Treg modalities. Herein, we have demonstrated that Foxp3+ Tregs potently suppress autoimmune responses in vivo through inhibition of the autophagic machinery in DCs in a cytotoxic T-lymphocyte-associated protein 4-dependent (CTLA4-dependent) manner. Autophagy-deficient DCs exhibited reduced immunogenic potential and failed to prime autoantigen-specific CD4+ T cells to mediate autoimmunity. Mechanistically, CTLA4 binding promoted activation of the PI3K/Akt/mTOR axis and FoxO1 nuclear exclusion in DCs, leading to decreased transcription of the autophagy component microtubule-associated protein 1 light chain 3β (Lc3b). Human DCs treated with CTLA4-Ig, a fusion protein ...
Design of efficacious Treg-based therapies and establishment of clinical tolerance in autoimmune diseases have proven to be challenging. The clinical implementation of Treg immunotherapy has been hampered by various impediments related to the stability and isolation procedures of Tregs as well as the specific in vivo targets of Treg modalities. Herein, we have demonstrated that Foxp3+ Tregs potently suppress autoimmune responses in vivo through inhibition of the autophagic machinery in DCs in a cytotoxic T-lymphocyte-associated protein 4-dependent (CTLA4-dependent) manner. Autophagy-deficient DCs exhibited reduced immunogenic potential and failed to prime autoantigen-specific CD4+ T cells to mediate autoimmunity. Mechanistically, CTLA4 binding promoted activation of the PI3K/Akt/mTOR axis and FoxO1 nuclear exclusion in DCs, leading to decreased transcription of the autophagy component microtubule-associated protein 1 light chain 3β (Lc3b). Human DCs treated with CTLA4-Ig, a fusion protein ...
Design of efficacious Treg-based therapies and establishment of clinical tolerance in autoimmune diseases have proven to be challenging. The clinical implementation of Treg immunotherapy has been hampered by various impediments related to the stability and isolation procedures of Tregs as well as the specific in vivo targets of Treg modalities. Herein, we have demonstrated that Foxp3+ Tregs potently suppress autoimmune responses in vivo through inhibition of the autophagic machinery in DCs in a cytotoxic T-lymphocyte-associated protein 4-dependent (CTLA4-dependent) manner. Autophagy-deficient DCs exhibited reduced immunogenic potential and failed to prime autoantigen-specific CD4+ T cells to mediate autoimmunity. Mechanistically, CTLA4 binding promoted activation of the PI3K/Akt/mTOR axis and FoxO1 nuclear exclusion in DCs, leading to decreased transcription of the autophagy component microtubule-associated protein 1 light chain 3β (Lc3b). Human DCs treated with CTLA4-Ig, a fusion protein ...
Design of efficacious Treg-based therapies and establishment of clinical tolerance in autoimmune diseases have proven to be challenging. The clinical implementation of Treg immunotherapy has been hampered by various impediments related to the stability and isolation procedures of Tregs as well as the specific in vivo targets of Treg modalities. Herein, we have demonstrated that Foxp3+ Tregs potently suppress autoimmune responses in vivo through inhibition of the autophagic machinery in DCs in a cytotoxic T-lymphocyte-associated protein 4-dependent (CTLA4-dependent) manner. Autophagy-deficient DCs exhibited reduced immunogenic potential and failed to prime autoantigen-specific CD4+ T cells to mediate autoimmunity. Mechanistically, CTLA4 binding promoted activation of the PI3K/Akt/mTOR axis and FoxO1 nuclear exclusion in DCs, leading to decreased transcription of the autophagy component microtubule-associated protein 1 light chain 3β (Lc3b). Human DCs treated with CTLA4-Ig, a fusion protein ...
Design of efficacious Treg-based therapies and establishment of clinical tolerance in autoimmune diseases have proven to be challenging. The clinical implementation of Treg immunotherapy has been hampered by various impediments related to the stability and isolation procedures of Tregs as well as the specific in vivo targets of Treg modalities. Herein, we have demonstrated that Foxp3+ Tregs potently suppress autoimmune responses in vivo through inhibition of the autophagic machinery in DCs in a cytotoxic T-lymphocyte-associated protein 4-dependent (CTLA4-dependent) manner. Autophagy-deficient DCs exhibited reduced immunogenic potential and failed to prime autoantigen-specific CD4+ T cells to mediate autoimmunity. Mechanistically, CTLA4 binding promoted activation of the PI3K/Akt/mTOR axis and FoxO1 nuclear exclusion in DCs, leading to decreased transcription of the autophagy component microtubule-associated protein 1 light chain 3β (Lc3b). Human DCs treated with CTLA4-Ig, a fusion protein ...
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T cells are the driving force that mediates graft-versus-host disease (GVHD) after transplantation. Thus, T cell suppression is key for GVHD treatment. Optimal T cell activation requires interaction between CD28, expressed on T cells, and CD80/CD86, expressed on antigen-presenting cells. Furthermore, activation of the metabolic regulator, mammalian target of rapamycin (mTOR) pathway, is critical for T cell function. Currently, there are FDA-approved medicines that inhibit CD80/CD86 (abatacept and belatacept) and mTOR (sirolimus). However, belatacept treatment unexpectedly led to increased acute organ rejection in a renal transplantation clinical trial, possibly by disrupting the checkpoint receptor cytotoxic T lymphocyte antigen 4, which also binds CD80/CD86. Whether blocking CD28 receptor specifically is a viable option for GVHD is not clear.. Watkins and colleagues evaluated the efficacy of a CD28-blocking antibody fragment (FR104) in a rhesus macaque GVHD model with hematopoietic stem cell ...
article{8be6ed91-fde0-42c0-8856-b5903bfbb308, abstract = {,p,CTLA-4 is important to down-regulating T cell responses and has been implicated in type 1 (insulin dependent) diabetes mellitus in both linkage and association studies. The aim of our study was to relate the polymorphic (AT)(n) microsatellite in the 3 untranslated sequence of the CTLA-4 gene to diabetes risk. We studied 616 consecutively diagnosed 0-34 year-old Swedish patients and 502 matched controls by PCR-based genotyping to determine the length of the 3-end (AT)(n)repeat region of the CTLA-4 gene and categorizing alleles as predominantly monomorphic short (S) or highly polymorphic (in length) long (L) alleles. The odds of type 1 diabetes of subjects with the L/L genotype was estimated to be 1.84 times that of subjects with the S/S genotype (95% CI 1.44-2.73, p=0.002). Further analysis of the long alleles, partitioned into intermediate (I) length and very long (VL) alleles, suggested that L alleles act recessively in conferring ...
TY - JOUR. T1 - Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. AU - Chen, Lieping. AU - Ashe, Stephanie. AU - Brady, William A.. AU - Hellström, Ingegerd. AU - Hellström, Karl Erik. AU - Ledbetter, Jeffrey A.. AU - McGowan, Patrick. AU - Linsley, Peter S.. PY - 1992/12/24. Y1 - 1992/12/24. N2 - Interaction of the B7 molecule on antigen-presenting cells with its receptors CD28 and CTLA-4 on T cells provides costimulatory signals for T cell activation. We have studied the effects of B7 on antitumor immunity to a murine melanoma that expresses a rejection antigen associated with the E7 gene product of human papillomavirus 16. While this E7+ tumor grows progressively in immunocompetent hosts, cotransfection of its cells with B7 led to tumor regression by a B7-dependent immune response mediated by CD8+ cytolytic T lymphocytes. The immune response induced by E7+B7+ tumor cells also caused regression of E7+ B7- tumors at distant sites and ...
Background: The anti-programmed cell death 1 (PD-1) antibody pembrolizumab is clinically active against non-small cell lung cancer (NSCLC). In addition to T-cells, human natural killer (NK) cells, reported to have the potential to prolong the survival of advanced NSCLC patients, also express PD-1. This study aimed to investigate the safety and efficacy of pembrolizumab plus allogeneic NK cells in patients with previously treated advanced NSCLC. Methods: In total, 109 enrolled patients with a programmed death ligand 1 (PD-L1) tumor proportion score (TPS) ≥1% were randomly allocated to group A (55 patients, pembrolizumab plus NK cells) and group B (54 patients, pembrolizumab alone). The patients received intravenous pembrolizumab (10 mg/kg) once every 3 weeks and continued treatment until the occurrence of tumor progression or unacceptable toxicity. The patients in group A continuously received two cycles of NK cell therapy as one course of treatment. Results: In our study, Group A patients had ...
Heppt, Markus V., Heinzerling, Lucie, Kähler, Katharina C., Forschner, Andrea, Kirchberger, Michael C., Loquai, Carmen, Meissner, Markus, Meier, Friedegund, Terheyden, Patrick, Schell, Beatrice, Herbst, Rudolf, Göppner, Daniela, Kiecker, Felix, Rafei-Shamsabadi, David, Haferkamp, Sebastian, Huber, Margit A., Utikal, Jochen, Ziemer, Mirjana, Bumeder, Irmgard, Pfeiffer, Christiane, Schäd, Susanne G., Schmid-Tannwald, Christoph, Tietze, Julia K., Eigentler, Thomas K. and Berking, Carola (2017) Prognostic factors and outcomes in metastatic uveal melanoma treated with programmed cell death-1 or combined PD-1/cytotoxic T-lymphocyte antigen-4 inhibition. European Journal of Cancer 82, pp. 56-65 ...
BACKGROUND Checkpoint inhibitor pneumonitis (CIP) is a highly morbid complication of immune checkpoint immunotherapy (ICI), one which precludes the continuation of ICI. Yet, the mechanistic underpinnings of CIP are unknown.METHODS To better understand the mechanism of lung injury in CIP, we prospectively collected bronchoalveolar lavage (BAL) samples in ICI-treated patients with (n = 12) and without CIP (n = 6), prior to initiating first-line therapy for CIP (high-dose corticosteroids). We analyzed BAL immune cell populations using a combination of traditional multicolor flow cytometry gating, unsupervised clustering analysis, and BAL supernatant cytokine measurements.RESULTS We found increased BAL lymphocytosis, predominantly CD4+ T cells, in patients with CIP. Specifically, we observed increased numbers of BAL central memory T cells, evidence of type I polarization, and decreased expression of cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1 in BAL Tregs, ...
Cancer and tumor cells are difficult to fight and require your body to generate a proper inflammatory response in order to clear them. However, the situation is made all the more difficult by cell markers that can induce tolerance in your T cells. These immune checkpoints are becoming hot topics for potential antibody therapies. Learn more these emerging factors with our Immune Checkpoints webpage. BioLegend develops and manufactures world-class, cutting-edge immunological reagents for biomedical research, offered at an outstanding value.
Dr Christian Blank - Netherlands Cancer Institute, Amsterdam, The Netherlands. Dr Blank speaks with ecancer at EADO 2017 about targeting immune checkpoints in melanoma patients with anti-PD1 and anti-CTLA-4 drugs.. Dr Blank describes how immune therapy is better suited to certain patient subtypes, and that combined checkpoint therapy may result in significant response or needless toxicity if applied without understanding the biology of the patient and cancer being treated.. Combinations of PD-1 and CTLA-4 targeted therapies were also discussed by Dr Christoph Hoeller, here.. ecancers filming has been kindly supported by Amgen through the ECMS Foundation. ecancer is editorially independent and there is no influence over content.. ...
Background Abatacept is a fusion protein of human CTLA-4 and the Fc portion of human IgG1. It is believed to be effective in the treatment of rheumatoid arthritis by blocking the co-stimulation of T-cells via blocking CD28-B7 interaction as CTLA-4 binds to both B7.1 (CD80) and B7.2 (CD86). However, the interaction of CD28 with B7 is crucial for the activation of naïve cells, whereas it is unclear whether the action of already activated CD4+ T-cells, which are readily present in established disease, also depend on this interaction. ...
Summary of Facts and Submissions. I. The proprietor (appellant) lodged an appeal against the decision of the opposition division to revoke European patent No. 0 865 293.. II. The patent was opposed on the grounds of lack of novelty and inventive step (Article 100(a) EPC), failure to provide a disclosure of the invention sufficiently clear and complete for it to be carried out by a person skilled in the art (Article 100(b) EPC) and because the subject-matter of the European patent extended beyond the content of the application as filed (Article 100(c) EPC).. III. The opposition division refused the main request (the claims as granted) because claims 3 to 7 were for subject-matter that extended beyond the content of the application as filed (Article 100(c) EPC). Auxiliary request 1 was refused because the subject-matter of claims 1, 3, 9 and 11 did not involve an inventive step (Article 100(a) EPC).. IV. With the statement of grounds of appeal, the appellant resubmitted the claims of former ...
La thérapie génique consiste à introduire du matériel génétique dans des cellules dans lobjectif de traiter une pathologie. Le plus souvent, la thérapie génique seffectue au moyen dun vecteur viral, transportant le gène jusque dans les cellules cibles. Dans le cas des maladies monogéniques, ladeno-associated virus (AAV) sest imposé progressivement comme un vecteur de choix. Son absence de pathogénicité, son large tropisme et sa capacité à transduire des cellules quiescentes sont autant davantages comparés à dautres vecteurs utilisés en thérapie génique. Lutilisation dAAV est approuvé en Europe pour le traitement dun déficit rare en lipoprotéine lipase et vient récemment dêtre approuvé par les autorités américaines pour le traitement dun déficit de la vision. Toutefois, les essais de thérapies géniques se heurtent souvent aux réponses immunitaires dirigées contre lAAV. En effet, les différents composants de ce vecteur viral ont été identifiés comme
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Easy to read patient leaflet for Ipilimumab. Includes indications, proper use, special instructions, precautions, and possible side effects.
Immunotherapy has led a transformation for melanoma care but combinations of anti–PD-1 and CTLA-4 agents are toxic and biomarkers are not available to help personalized treatment, calling for further research into less toxic and more effective options.
产品名称:Anti-Mouse/RatIL-17APEeBio17B7规格:50ug货号:12-7177-81厂商:eBioscience产品介绍:Alsoknownas:Interleukin-17A,CytotoxicT-lymphocyte-associatedantigen8,CTLA-8Clone:eBio17B7HostRatIsotypeIgG2a,kappaReactivityMo
The results of genetic association studies regarding cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) polymorphisms and digestive system malignancies were controversial. The authors designed this meta-analysis to more precisely estimate relationships between CTLA-4 polymorphisms and digestive system malignancies by pooling the results of related studies. The authors searched PubMed, Embase, Web of Science, and CNKI for eligible studies. Thirty-one eligible studies were pooled analyzed in this meta-analysis. The pooled meta-analysis results showed that genetic distributions of rs231775, rs4553808, and rs733618 polymorphisms among patients with digestive system malignancies and controls differed significantly. Moreover, genotypic distribution differences were also observed for rs231775 polymorphism among patients with colorectal cancer/pancreatic cancer and controls, for rs4553808 and rs5742909 polymorphisms among patients with gastric cancer and controls, for rs3087243 polymorphism among patients
TY - JOUR. T1 - Cardiovascular toxicities associated with immune checkpoint inhibitors. AU - Hu, Jiun Ruey. AU - Florido, Roberta. AU - Lipson, Evan. AU - Naidoo, Jarushka. AU - Ardehali, Reza. AU - Tocchetti, Carlo G.. AU - Lyon, Alexander R.. AU - Padera, Robert F.. AU - Johnson, Douglas B.. AU - Moslehi, Javid. PY - 2019/4/15. Y1 - 2019/4/15. N2 - Cardiovascular toxicities associated with immune checkpoint inhibitors (ICIs) have been reported in case series but have been underappreciated due to their recent emergence, difficulties in diagnosis and non-specific clinical manifestations. ICIs are antibodies that block negative regulators of the T cell immune response, including cytotoxic T lymphocyte-associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1), and PD-1 ligand (PD-L1). While ICIs have introduced a significant mortality benefit in several cancer types, the augmented immune response has led to a range of immune-related toxicities, including cardiovascular toxicity. ...
Title: Anti-CTLA4 Monoclonal Antibody Ipilimumab in the Treatment of Metastatic Melanoma: Recent Findings. VOLUME: 3 ISSUE: 2. Author(s):Marko Lens, Pier F. Ferrucci and Alessandro Testori. Affiliation:Kings College, Genetic Epidemiology Unit, St. Thomas Hospital, Lambeth Palace Road, London SE1 7EH, United Kingdom.. Keywords:CTLA-4, melanoma, antibody, ipilimumab, anti-tumour. Abstract: Use of monoclonal anti-CTLA4 antibodies represents a new promising strategy to block the activation of immunosuppressive CTLA-4 and thus induce tumour regression. This review is mainly focused on the report of existing data on the clinical use of Ipilimumab (formerly MDX-010) in the treatment of metastatic melanoma. Several phase I and II trials have been conducted to evaluate safety and efficacy of this form of immunotherapy either alone or in combination with vaccines or chemotherapy in patients with stage III or stage IV melanoma. Results from these studies are presented, patented and discussed. The ...
... Roser Calvo* Patient Safety, Safety Science, AstraZeneca Pharmaceuticals, Gaithersburg, MD, United States Immune-related hematological adverse events are amongst the rare but potentially life-threatening complications of immune checkpoint inhibitors. The spectrum of these toxicities ...
This is a multicentered, open label, randomized phase II trial of PROSTVAC or ipilimumab or the combination of PROSTVAC and ipilimumab as neoadjuvant therapy in patients with localized PC. Eligible patients will be randomized to PROSTVAC monotherapy (Arm A), ipilimumab monotherapy (Arm B), or combination therapy with both PROSTVAC and ipilimumab (Arm C), prior to RP. In arms A and C, PROSTVAC-V will be administered subcutaneously as the primary vaccine on Day 1, which will be followed 2 weeks later with a series of 2 PROSTVAC-F subcutaneous administrations, given 3 weeks apart. In arms B and C, ipilimumab will be administered twice, at a dose of 3mg/kg, 3 weeks apart. In the combination arm, ipilimumab administration will coincide with the PROSTVAC-F administration. In arm B, ipilimumab will begin on Day 1. In all three arms, RP will occur 21 days, or three weeks, following final treatment administration of PROSTVAC or ipilimumab. No further therapy will be administered on study following ...
A recent study that investigates the effects of anti-CTLA-4 antibody on the number and types of T cells present in a patients blood. The results, which appear in the journal Science Translational Medicine, shed light on the mechanism of action of this type of cancer immunotherapy and suggest that immune repertoire sequencing could be used to predict which patients will have improved survival in response to treatment.. "Immune repertoire sequencing is a new tool that allows us to assess the totality and complexity of immune responses in ways not previously possible," said Lawrence Fong, M.D., Professor, Division of Hematology/Oncology, Department of Medicine, UCSF. "Our analysis of anti-CTLA-4 antibody treated patients using the LymphoSIGHT platform revealed that this therapy induces profound turnover and large-scale remodeling of the entire human T cell repertoire. These findings have implications for understanding how cancer immunotherapy works, which patients will benefit, and the etiology of ...
Immune checkpoint inhibitors work to block two proteins - PD-1 or CTLA-4 - that cancer cells use to evade immune system protector cells called T-cells.
Although early cutaneous melanoma is usually curable with surgery, distant metastatic melanoma is an aggressive cancer with a median overall survival time of less than 1 year. In 2012, over 75,000 new melanoma diagnoses were expected and over 9,000 deaths were projected (1). Advances in the understanding of distinct melanoma subtypes as well as melanoma immunobiology have resulted in 2 FDA-approved therapies for metastatic melanoma in 2011: vemurafenib, an inhibitor of mutant BRAF - an oncogene present in approximately 50% of melanomas - and ipilimumab, a monoclonal antibody that targets CTLA-4 (2-4)…". ...
A new study found that cancer patients with a pre-existing autoimmune disease receiving immune checkpoint inhibitors as treatment are likely to experience a flare.
Title:The Breakthroughs in Cancer Immune Checkpoint Based Therapy: A Review of Development in Immune Checkpoint Study and its Application. VOLUME: 20 ISSUE: 5. Author(s):Yao Huang, Dong Liang, Jingfeng Liu, Jinhua Zeng and Yongyi Zeng*. Affiliation:Xihong Road 312, Fuzhou 350025, Fujian Province, Xihong Road 312, Fuzhou 350025, Fujian Province, Xihong Road 312, Fuzhou 350025, Fujian Province, Xihong Road 312, Fuzhou 350025, Fujian Province, Xihong Road 312, Fuzhou 350025, Fujian Province. Keywords:Immunotherapy, immune checkpoint inhibitors, PD-1, cancer, immune checkpoint therapy, hematological malignancies.. Abstract:Recently, immunotherapy has attracted more attentions to fight cancer due to its selectivity, long lasting effects, and demonstrated better overall survival and tolerance, when compared to patients treated with conventional chemotherapy or radiotherapy alone. The anti-tumor response of patient with cancer is improved either by increasing the effector cell number, the production of ...
The Small Cell Lung Cancer Treatment Market is driven by the launch of premium-priced therapies, including anti-PD-1 and anti-CTLA-4 immunotherapies and targeted agents. The market growth is estimated to occur across the seven major markets of the US, France, Germany, Italy, Spain, the UK, and Japan.. Browse Detailed Toc, Tables, Figures, Charts and Companies Mentioned in Small Cell Lung Cancer Treatment Market ResearchReport at- http://www.absolutereports.com/opportunityanalyzer-small-cell-lung-cancer-sclc-opportunity-analysis-and-forecasts-to-2024-10112598. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor "Yervoy" will be the first immunotherapy to be introduced in the market. This drug is being developed by Bristol-Myers Squibb and will be launched in 2016 across the seven major markets.. The increase in rates of the disease across the five European markets and Japan, at a CAGR of 1.49% over the forecast period is estimated to further bolster the Small Cell Lung Cancer treatment ...
Small cell lung cancer (SCLC) and malignant pleural mesothelioma (MPM) are historically characterized by a disappointing lack of significant therapeutic breakthroughs for novel agents and both malignancies represent true unmet medical needs. Given promising results of anti-CTLA-4 and anti-PD-1/PD-L1 antibodies in the treatment of advanced non-small cell lung cancers, these immune checkpoint inhibitors are now also under investigation in SCLC and MPM, as well as in thymic epithelial tumors (TETs). Here, we review the biological and clinical rationale for immune checkpoint inhibition in SCLC, MPM and TETs, and present preliminary clinical results with available antibodies. Immunotherapeutic perspectives for these malignancies in terms of novel agents currently under evaluation or anticipated in the near future are also discussed. Current immune checkpoint blockers targeting CTLA-4 and the PD-1/PD-L1 axis, administered alone or in combination and as multimodality treatment, are likely to be a ...
The presence of TILs has been shown to be a favorable prognostic indicator in a number of cancers, and gene expression profiling demonstrated that patients with high baseline tumor expression of genes related to both innate and adaptive immune response were more likely to favorably respond to immunotherapy (7, 23, 24). The presence of TILs in tumors has been shown to be associated with type I IFN transcriptional profile, and additional studies demonstrated the critical role for type I IFN in CD8a+ DC-mediated antigen cross-presentation and priming of tumor-specific CD8+ T cells (8, 9). These findings provide a strong rationale to explore tumor therapeutic strategies that activate the type I IFN pathway. Indeed, combination therapy using intratumoral CpG oligonucleotides with antibodies targeting immune checkpoints has been shown to be an effective therapeutic strategy resulting in depletion of Tregs at the injected tumor site and in regression of distant tumors (25).. Here, to trigger ...
Acronyms and Abbreviations BIR, baculovirus inhibitor of apoptosis repeat; CARD, caspase activating and recruitment domain; CD, cluster of differentiation; cGAS, cyclic AMP/GMP synthetase; CTLA, cytotoxic T-lymphocyte antigen; DAI, DNA-dependent activator of IRFs; ERK, extracellular signal-regulated kinase; FADD, Fas-associated death domain; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-monocyte colony-stimulating factor; IFN, interferon; IκB; inhibitor of κB; IKK, IκB kinase; IL, interleukin; IPAF, ice-protease activating factor; IPS-1, IFN-β promoter stimulator 1; IRAK, interleukin-1 receptor-associated kinase; IRF, interferon response factor; JAK, Janus kinase; JNK, c-Jun N-terminal kinase; LPS, lipopolysaccharide; LRR, leucine-rich repeat; MAL, MyD88 adaptor-like; MDA5, melanoma differentiation-associated gene 5; MDP, muramyl dipeptide; MyD88, myeloid differentiation primary response 88; NACHT, a nucleotide-binding domain present in NAIP, CIITA, HET-E, and TP-1; ...
Cell 2018 Dec 13; 175(7):1731-1743.e13. While checkpoint immunotherapy has yielded unprecedented results in patients with advanced stage cancers, only a fraction of patients experience a strong response, leading investigators to examine mechanisms of resistance, novel molecular targets and combination therapies. Andre et al. characterizes the first-in-class immune checkpoint inhibitor, monalizumab, which targets NKG2A to promote anti-tumor immunity by enhancing the activities of both T and NK cells. This study demonstrates how NKG2A blockade enhances the anti-tumor immunity mediated by NK and CD8+ T cells when used as both a single agent or in combination with other monoclonal antibodies and highlights the potential of critical immune checkpoints other than PD-1 and CTLA-4.. "CAR T cells targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors," by Robbie G. Majzner et al ...
Background: Three genes have been confirmed as major joint susceptibility genes for endocrine autoimmune disease: human leukocyte antigen class II, cytotoxic T-lymphocyte antigen 4 and protein tyrosine phosphatase non-receptor type 22. Recent studies showed that a genetic variation within the interferon induced helicase domain 1 (IFIH1) locus (rs1990760 polymorphism) is an additional risk factor in type 1 diabetes and Graves disease (GD). Methods: The aim of the present study was to investigate the role of the rs1990760 polymorphism within the IFIH1 gene in German patients with GD (n = 258), Hashimotos thyroiditis (HT, n = 106), Addisons disease (AD, n = 195) and healthy controls (HC, n = 227) as well as in 55 GD families (165 individuals, German) and 100 HT families (300 individuals, Italian). Furthermore, the interaction between rs1990760 polymorphism with human leukocyte antigen (HLA) risk haplotype DQ2(DQA*0501-DQB*0201), the risk haplotypes DQ2/DQ8 (DQA*0301-DQB*0302) and the status of ...

Phase 3, randomised, open-label study of durvalumab (MEDI4736) in combination with tremelimumab versus platinum-based...Phase 3, randomised, open-label study of durvalumab (MEDI4736) in combination with tremelimumab versus platinum-based...

The blockade of immune checkpoints, such as programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 ( ... CTLA-4), is a promising novel approach in cancer treatment. As these pathways are non-redundant, dual targeting may have ... and tremelimumab is a selective human IgG2 mAb inhibitor of CTLA-4. In a Phase 1b study (NCT02000947), durvalumab + ... T. Mok1, P. Schmid2, O. Aren3, O. Arrieta4, M. Gottfried5, A.R. Jazieh6, R. Ramlau7, C. Timcheva8, C. Martin9, L. Zhao10, S. ...
more infohttp://oncologypro.esmo.org/Topics/Cancer-Immunology-and-Immunotherapy/Phase-3-randomised-open-label-study-of-durvalumab-MEDI4736-in-combination-with-tremelimumab-versus-platinum-based-chemotherapy-in-first-line-treatment-of-patients-with-advanced-or-metastatic-NSCLC-NEPTUNE

CTLA-4 blockade increases antigen-specific CD8(+) T cells in prevaccinated patients with melanoma: three cases.  - PubMed - NCBICTLA-4 blockade increases antigen-specific CD8(+) T cells in prevaccinated patients with melanoma: three cases. - PubMed - NCBI

Vaccination induced a measurable antigen-specific T-cell response that increased following CTLA-4 blockade, potentially " ... CTLA-4 blockade increases antigen-specific CD8(+) T cells in prevaccinated patients with melanoma: three cases.. Yuan J1, ... Tumor escape may be related to antigen loss or lack of MHC expression necessary for immune activity. These results in a limited ... CTLA-4 blockade increases antigen-specific CD8+ T-cells in prevaccinated patients with melanoma: three cases ...
more infohttps://www.ncbi.nlm.nih.gov/pubmed/21465316

Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis.  - PubMed - NCBICytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis. - PubMed - NCBI

Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis.. Agarwal K1, ... The CTLA-4 G allele is more common in patients with type 1 autoimmune hepatitis and may represent a second susceptibility ... To determine the frequency and significance of the exon 1 adenine (A)-guanine (G) base-exchange polymorphism for CTLA-4 in ... The gene encoding cytotoxic T-lymphocyte antigen-4 (CTLA-4) on chromosome 2q33 may also influence autoimmunity. ...
more infohttps://www.ncbi.nlm.nih.gov/pubmed/10613727?dopt=Abstract

Cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates primary and secondary peptide-specific CD4+ T cell responses | PNASCytotoxic T lymphocyte antigen-4 (CTLA-4) regulates primary and secondary peptide-specific CD4+ T cell responses | PNAS

antigen-presenting cell;. ELISPOT,. enzyme-linked immunospot assay;. CTLA-4,. cytotoxic T lymphocyte antigen-4. ... Most of the CD4+ T cells in the AND TCR+ CTLA-4+ mice had a naive phenotype and were CD44lo, MEL14hi, CD45RBhi (Fig. 1B). In ... The CTLA-4+/− mice were crossed to an MHC class II-restricted TCR (AND TCR) (Vβ3Vα11) transgenic mouse strain that is selected ... The expected skewing toward CD4+ T cells was observed in the AND TCR+ CTLA-4+/+ or CTLA-4+/− (AND TCR+ CTLA-4+) mice, and ,90% ...
more infohttps://www.pnas.org/content/96/15/8603?ijkey=b89786bdc496410e46f3ef708626bd113315337d&keytype2=tf_ipsecsha

T Lymphocyte Activation Antigen CD80 (Activation B7-1 Antigen or CTLA 4 Counter Receptor B7.1 or CD80) - Pipeline Review, H2...T Lymphocyte Activation Antigen CD80 (Activation B7-1 Antigen or CTLA 4 Counter Receptor B7.1 or CD80) - Pipeline Review, H2...

Activation B7-1 Antigen or CTLA 4 Counter Receptor B7. ... T Lymphocyte Activation Antigen CD80 (Activation B7-1 Antigen ... T Lymphocyte Activation Antigen CD80 (Activation B7-1 Antigen or CTLA 4 Counter Receptor B7.1 or CD80) - Pipeline Review, H2 ... T Lymphocyte Activation Antigen CD80 (Activation B7-1 Antigen or CTLA 4 Counter Receptor B7.1 or CD80) - Cluster of ... T Lymphocyte Activation Antigen CD80 (Activation B7-1 Antigen or CTLA 4 Counter Receptor B7.1 or CD80) pipeline Target ...
more infohttps://www.reportbuyer.com/product/5227151/t-lymphocyte-activation-antigen-cd80-activation-b7-1-antigen-or-ctla-4-counter-receptor-b7-1-or-cd80-pipeline-review-h2-2018.html

Lack of correlation between the levels of soluble cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and the CT-60 genotypes ...Lack of correlation between the levels of soluble cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and the CT-60 genotypes ...

... plays a critical role in downregulation of antigen-activated immune response and polymorphisms at the CTLA-4 gene have been ... that is believed to control the processing and production of soluble CTLA-4 (sCTLA-4). We therefore determined sCTLA-4 protein ... Higher levels of sCTLA-4 were observed in T1D (2.24 ng/ml) and AbP (mean = 2.17 ng/ml) subjects compared to AbN controls (mean ... Consistent with the higher serum sCTLA-4 levels observed in other autoimmune diseases, our results suggest that sCTLA-4 may be ...
more infohttps://jautoimdis.biomedcentral.com/articles/10.1186/1740-2557-2-8/tables/1

Rigid-body Ligand Recognition Drives Cytotoxic T-lymphocyte Antigen 4 (CTLA-4) Receptor Triggering - NDM Research BuildingRigid-body Ligand Recognition Drives Cytotoxic T-lymphocyte Antigen 4 (CTLA-4) Receptor Triggering - NDM Research Building

Rigid-body Ligand Recognition Drives Cytotoxic T-lymphocyte Antigen 4 (CTLA-4) Receptor Triggering ... Rigid-body Ligand Recognition Drives Cytotoxic T-lymphocyte Antigen 4 (CTLA-4) Receptor Triggering ... Rigid-body Ligand Recognition Drives Cytotoxic T-lymphocyte Antigen 4 (CTLA-4) Receptor Triggering ...
more infohttps://www.ndmrb.ox.ac.uk/research/our-research/publications/120121

Intracellular Trafficking of CTLA-4 and Focal Localization Towards Sites of TCR Engagement - PubMedIntracellular Trafficking of CTLA-4 and Focal Localization Towards Sites of TCR Engagement - PubMed

CTLA-4 functions at the cell surface, yet is primarily localized in intracellular vesicles. Here, we demonstrate cycling of ... T lymphocyte receptor CTLA-4 binds costimulatory molecules CD80 (B7-1) and CD86 (B7-2) with high avidity and negatively ... Receptors, Antigen, T-Cell / metabolism *. Actions. * Search in PubMed * Search in MeSH ... Intracellular Trafficking of CTLA-4 and Focal Localization Towards Sites of TCR Engagement P S Linsley 1 , J Bradshaw, J Greene ...
more infohttps://pubmed.ncbi.nlm.nih.gov/8673700/

Resveratrol and Curcumin Suppress Immune Response Through CD28/CTLA-4 and CD80 Co-Stimulatory Pathway - PubMedResveratrol and Curcumin Suppress Immune Response Through CD28/CTLA-4 and CD80 Co-Stimulatory Pathway - PubMed

Activation of T cells requires co-stimulation, in addition to signals through the antigen-receptor complex. Antigen encounter ... Resveratrol and Curcumin Suppress Immune Response Through CD28/CTLA-4 and CD80 Co-Stimulatory Pathway S Sharma 1 , K Chopra, S ... Resveratrol and Curcumin Suppress Immune Response Through CD28/CTLA-4 and CD80 Co-Stimulatory Pathway S Sharma et al. Clin Exp ... Effect of resveratrol (RVT) and curcumin (CMN) on the expression of CD28 and CTLA-4. RVT and CMN were added in different ...
more infohttps://pubmed.ncbi.nlm.nih.gov/17177975/

Treatment with anti-CTLA-4 greatly enhances IL-5 prod | Open-iTreatment with anti-CTLA-4 greatly enhances IL-5 prod | Open-i

Treatment with anti-CTLA-4 greatly enhances IL-5 production in lymph nodes draining the sites of infection with Nb. C57BL/6 ... The ability of CTLA-4 blockade to accelerate primary immune responses to a protective level during an acute infection indicates ... The ability of CTLA-4 blockade to accelerate primary immune responses to a protective level during an acute infection indicates ... Bottom Line: We used a neutralizing antibody to block CTLA-4 interaction with its ligands CD80 and CD86 during infection of ...
more infohttps://openi.nlm.nih.gov/detailedresult.php?img=PMC2198990_JEM.970535f1&req=4

Adhesion to target cells is disrupted by the killer cell inhibitory receptor.Adhesion to target cells is disrupted by the killer cell inhibitory receptor.

Antigens, CD. Antigens, CD28 / immunology, physiology. Antigens, Differentiation / pharmacology. CTLA-4 Antigen. Cell Adhesion ... 0/Antibodies; 0/Antigens, CD; 0/Antigens, CD28; 0/Antigens, Differentiation; 0/CTLA-4 Antigen; 0/CTLA4 protein, human; 0/HLA-C ... Antigens; 0/HLA-C*02 antigen; 0/HLA-C*03 antigen; 0/Immunoconjugates; 0/Intracellular Signaling Peptides and Proteins; 0/ ... HLA-C Antigens / genetics, physiology. Humans. Immunoconjugates*. Intracellular Signaling Peptides and Proteins. Killer Cells, ...
more infohttp://www.biomedsearch.com/nih/Adhesion-to-target-cells-disrupted/10898979.html

Novel and Emerging Therapies for Cholestatic Liver DiseasesNovel and Emerging Therapies for Cholestatic Liver Diseases

ASBT, Apical sodium-dependent bile acid transporter; CX3CL1, chemokine (C-X3-C motif) ligand 1; CTLA-4, cytotoxic T-lymphocyte ... Multifactorial; genetic susceptibility, immune mediated with loss of tolerance to self-antigen (pyruvate dehydrogenase complex ... Table 4. Active clinical trials for PSC a Mechanism. Drug. Primary outcomes. Phase. Clinical trial/EudraCT number. ... antigen 4; EudraCT, European clinical trials database; FXR, farnesoid X receptor; IgG1, immunoglobulin G1; NADPH, nicotinamide ...
more infohttps://www.medscape.com/viewarticle/902289

MEDLINE - Resultado p gina 1
	MEDLINE - Resultado p gina 1

0 (Antigens, Bacterial); 0 (Antigens, Neoplasm); 0 (Antigens, Viral); 0 (Biomarkers, Tumor); 0 (CTLA-4 Antigen); 0 (Epitopes, T ... 0 (Antigens, Bacterial); 0 (Drug Carriers); 0 (Escherichia coli Proteins); 0 (K88 antigen, E coli); 0 (Plant Lectins); 0 ( ... Ant geno CTLA-4/antagonistas & inibidores. C lulas Dendr ticas/imunologia. Epitopos de Linf cito T/imunologia. Seres Humanos. ... In the current study, we assessed serum IgA binding to the B. burgdorferi peptide antigens, C6, the target of the FDA-cleared ...
more infohttp://bases.bireme.br/cgi-bin/wxislind.exe/iah/online/?IsisScript=iah/iah.xis&nextAction=lnk&base=MEDLINE&lang=p&format=detailed.pft&indexSearch=EX&exprSearch=D23.050.161

MEDLINE - Resultado p gina 1
	MEDLINE - Resultado p gina 1

Ant geno CTLA-4/imunologia. Doen as do Sistema Digest rio/etiologia. Doen as do Sistema End crino/etiologia. Seres Humanos. ... Development and application of anti-CTLA-4 antibody and anti-PD-1 antibody to cancer immunotherapy brought great survival ... 0 (Antibodies, Monoclonal); 0 (CTLA-4 Antigen); 0 (Ipilimumab); 0 (PDCD1 protein, human); 0 (Programmed Cell Death 1 Receptor ... Average age was 28,4 5,5 years. A retrospective analysis of the causes of calls to pregnant ambulance carriages was carried out ...
more infohttp://bases.bireme.br/cgi-bin/wxislind.exe/iah/online/?IsisScript=iah/iah.xis&nextAction=lnk&base=MEDLINE&lang=p&format=detailed.pft&indexSearch=EX&exprSearch=C06

CTLA-4 gene polymorphisms in systemic lupus erythematosus: a highly significant association with a determinant in the promoter...CTLA-4 gene polymorphisms in systemic lupus erythematosus: a highly significant association with a determinant in the promoter...

This is the first report to our knowledge implicating CTLA-4 genotypes at the -1722 locus in susceptibility to any disease. ... Particular genotypes of the locus encoding the CTLA-4 glycoprotein have been associated with susceptibility to various ... CTLA-4; CD 152) is a negative regulator of T-lymphocyte activation. ... The cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4; CD 152) is a negative regulator of T-lymphocyte activation. Particular ...
more infohttps://www.semanticscholar.org/paper/CTLA-4-gene-polymorphisms-in-systemic-lupus-a-with-Hudson-Rocca/62c5146606de10d5947919c119e433382bda37bf

Frontiers | Targeting Tumor Metabolism: A New Challenge to Improve Immunotherapy | ImmunologyFrontiers | Targeting Tumor Metabolism: A New Challenge to Improve Immunotherapy | Immunology

Intriguingly, the upregulation of tumor PD-L1 and CTLA-4 alters the metabolic programme of T cells and drives their exhaustion ... Intriguingly, the upregulation of tumor PD-L1 and CTLA-4 alters the metabolic programme of T cells and drives their exhaustion ... chimeric-antigen receptor; CTLs, cytolytic T cells; CTLA-4, cytotoxic T-lymphocyte antigen; FAO, fatty acid oxidation; HIF, ... CTLA-4 and PD1 are critical coinhibitory receptors highly expressed in T cells under TME (86). Moreover, PD-1 ligands PD-L1 and ...
more infohttps://www.frontiersin.org/articles/10.3389/fimmu.2018.00353/full

Regulatory CD4+CD25+ T Cells Restrict Memory CD8+ T Cell Responses | JEMRegulatory CD4+CD25+ T Cells Restrict Memory CD8+ T Cell Responses | JEM

... anti-CD152/CTL-associated antigen (CTLA-4) mAb (9H10), anti-IFN-γ mAb (clone: R4-6A2, IgG1), and anti-TGF-β mAb (2G7) were ... 3 C). Antigen-specific cytotoxicity was only detected in cells from anti-CD4 mAb-treated mice. In contrast to the tetramer and ... Consequently, the enhanced CD8+ T cell response could be due to an increase in antigen load. Although we did not observe a ... Anti-CD4 mAb Treatment Does Not Induce LLO91-99-specific CD8+ Memory T Cell Proliferation in the Absence of Antigen Stimulation ...
more infohttp://jem.rupress.org/content/196/12/1585

TP53 Mutation as Potential Negative Predictor for Response of Anti-CTLA-4 Therapy in Metastatic Melanoma - PubMedTP53 Mutation as Potential Negative Predictor for Response of Anti-CTLA-4 Therapy in Metastatic Melanoma - PubMed

In the present study, we examined the relationship between TP53 mutation and response to CTLA-4 blockade in metastat … ... Blockade of cytotoxic T-lymphocyte antigen-4 as a new therapeutic approach for advanced melanoma. Wang XY, Zuo D, Sarkar D, ... Wenjing Xiao 1 , Nan Du 2 , Taoyuan Huang 3 , Jinan Guo 4 , Xingkui Mo 5 , Tao Yuan 5 , Yong Chen 6 , Ting Ye 7 , Chunwei Xu 8 ... Wenjing Xiao 1 , Nan Du 2 , Taoyuan Huang 3 , Jinan Guo 4 , Xingkui Mo 5 , Tao Yuan 5 , Yong Chen 6 , Ting Ye 7 , Chunwei Xu 8 ...
more infohttps://phgkb.cdc.gov/PHGKB/phgHome.action?action=forward&dbsource=huge&id=164696

Two SNPs in the Promoter Region of the CTLA-4 Gene Affect Binding of Transcription Factors and Are Associated With Human...Two SNPs in the Promoter Region of the CTLA-4 Gene Affect Binding of Transcription Factors and Are Associated With Human...

Baniasadi V, Narain N, Goswami R, Das SN. Baniasadi V, et al. Tissue Antigens. 2006 May;67(5):383-9. doi: 10.1111/j.1399- ... No association of CTLA-4 polymorphisms with susceptibility to Behçet disease. Du L, Yang P, Hou S, Zhou H, Kijlstra A. Du L, et ... Studies on the genetic pathogenesis of myasthenia gravis caused by CTLA-4 gene polymorphism]. Mao HT, Wang XB, Zhang L, Gu HT. ... Identification of CTLA-4 isoforms produced by alternative splicing and their association with myasthenia gravis. Gu M, ...
more infohttps://phgkb.cdc.gov/PHGKB/phgHome.action?action=forward&dbsource=huge&id=33017

Genotype analysis of polymorphisms in autoimmune susceptibility genes, CTLA-4 and PTPN22, in an Acute anterior uveitis cohort<...Genotype analysis of polymorphisms in autoimmune susceptibility genes, CTLA-4 and PTPN22, in an Acute anterior uveitis cohort<...

Protein tyrosine phosphatase type 22 (PTPN22) and Cytotoxic T lymphocyte antigen-4 (CTLA-4) are two of these genes, and single ... Results: There was no significant association between PTPN22 620W, CTLA-4 -318C/T, or CTLA-4 49A/G and AAU. Similarly, there ... Results: There was no significant association between PTPN22 620W, CTLA-4 -318C/T, or CTLA-4 49A/G and AAU. Similarly, there ... Results: There was no significant association between PTPN22 620W, CTLA-4 -318C/T, or CTLA-4 49A/G and AAU. Similarly, there ...
more infohttps://ohsu.pure.elsevier.com/en/publications/genotype-analysis-of-polymorphisms-in-autoimmune-susceptibility-g-2

HKU Scholars Hub: Association of CTLA-4 gene microsatellite polymorphism with ulcerative colitis in Chinese patientsHKU Scholars Hub: Association of CTLA-4 gene microsatellite polymorphism with ulcerative colitis in Chinese patients

Cytotoxic T lymphocyte associated antigen-4 (CTLA-4), expressed mainly in activated T cells, inhibits T cell activation and ... Polymorphisms of the CTLA-4 gene are known to be associated with several autoimmune diseases. The aim of this study was to ... Polymorphisms of the CTLA-4 gene are known to be associated with several autoimmune diseases. The aim of this study was to ... Article: Association of CTLA-4 gene microsatellite polymorphism with ulcerative colitis in Chinese patients. *Show simple item ...
more infohttp://repository.hku.hk/handle/10722/78391

Estimating the kon and koff for sCD80 binding CTLA-4 Ig | Open-iEstimating the kon and koff for sCD80 binding CTLA-4 Ig | Open-i

Estimating the kon and koff for sCD80 binding CTLA-4 Ig. (A) Example of primary data. sCD80 (265 nM) was injected (solid bar) ... and modulate T cell antigen recognition. Preliminary reports have suggested that CD80 binds CTLA-4 and CD28 with affinities (Kd ... and modulate T cell antigen recognition. Preliminary reports have suggested that CD80 binds CTLA-4 and CD28 with affinities (Kd ... In the present study, we use surface plasmon resonance to measure the affinity and kinetics of CD80 binding to CD28 and CTLA-4 ...
more infohttps://openi.nlm.nih.gov/detailedresult.php?img=PMC2196039_JEM.vandermerwe4&req=4

Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4...Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4...

Cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates primary and secondary peptide-specific CD4(+) T cell responses. Proc. Natl ... d) Suppression of 50,000 CTLA-4−/− CD4+CD25− T cells by WT or CTLA-4−/− CD4+CD25+ T reg cells. Data in a-d represent three ... Suppression of CTLA-4−/− CD4+CD25− T cells by CTLA-4−/− T reg cells was virtually nonexistent in contrast to the full ... CTLA-4 blockade reverses CD8+ T cell tolerance to tumor by a CD4+ T cell- and IL-2-dependent mechanism. Immunity. 11:483-493. ...
more infohttp://jem.rupress.org/content/206/8/1717?ijkey=87b67ffd85ead1ce63fa0f4d54e9976abe9238ae&keytype2=tf_ipsecsha

Frontiers | The Identification of Immunological Biomarkers in Kidney Cancers | OncologyFrontiers | The Identification of Immunological Biomarkers in Kidney Cancers | Oncology

Neo-antigen loss and growth of a subclone lacking the neo-antigen eliciting the immune response are both potential explanations ... Blockade of CTLA-4 (by anti-CTLA-4) and PD-1 (anti-PD-1) or PD-L1 stimulates effector T cells to produce antitumor responses. ... CTLA-4 competes with CD28 (costimulatory T cell molecule) for B7 ligands (CD80 and CD86 that are not shown in the figure) and ... Defects in antigen presentation, such as mutations in the β-2 microglobulin gene, have also been identified as a mechanism of ...
more infohttps://www.frontiersin.org/articles/10.3389/fonc.2018.00456/full

Vitiligo, reactive oxygen species and T-cells | Clinical ScienceVitiligo, reactive oxygen species and T-cells | Clinical Science

... cutaneous lymphocyte-associated antigen; CTL, cytotoxic T-lymphocyte; CTLA-4, CTL antigen-4; CYP, cytochrome P450; DC, ... Sensitized CD8+ T-cells are targeted to melanocyte differentiation antigens and destroy melanocytes either as the primary event ... human leucocyte antigen; ICAM, intercellular adhesion molecule; IFN, interferon; IL, interleukin; iNOS, inducible NO synthase; ... Abbreviations: α-MSH, α-melanocyte-stimulating hormone; 4-TBP, 4-tertiary butyl phenol; 6BH4, (6R)-L-erythro-5,6,7,8,- ...
more infohttp://www.clinsci.org/content/120/3/99
  • The nature of TCR-ligand interaction that initiates the lymphoproliferation and the extent to which individual naive CD4 + T cells become dysregulated by the absence of CTLA-4 in vivo is unknown. (pnas.org)
  • The recent observation that neutralization or genetic deletion of the T lymphocyte receptor CTLA-4 allows enhanced T cell reactivity offers new opportunities for immunotherapy against infectious agents. (nih.gov)
  • Rat Ig, anti-CD16/CD32 mAb (2.4G2), anti-CD8α mAb (YTS169), anti-CD4 mAbs (YTS191.1 and GK1.5), anti-CD25 mAb (PC61), anti-CD62L mAb (Mel-14), anti-CD152/CTL-associated antigen (CTLA-4) mAb (9H10), anti-IFN-γ mAb (clone: R4-6A2, IgG1), and anti-TGF-β mAb (2G7) were purified from rat serum or hybridoma supernatants with protein G sepharose. (rupress.org)
  • The molecular mechanisms underlying the regulation of the CD152 (CTLA-4) gene are largely unknown. (cdc.gov)
  • To examine the effect of restricting the CD4 + TCR repertoire on the phenotype of CTLA-4-deficient mice and to assess the influence of CTLA-4 on peptide-specific CD4 + T cell responses in vitro , an MHC class II-restricted T cell receptor (AND TCR) transgene was introduced into the CTLA-4 −/− animals. (pnas.org)
  • These results demonstrate that CTLA-4 is a key regulator of peptide-specific CD4 + T cell responses and support the model that CTLA-4 plays a differential role in maintaining T cell homeostasis of CD4 + vs. CD8 + T cells. (pnas.org)
  • Surprisingly, anti-CD4 mAb treatment during secondary CD8 + T cell responses markedly enlarged the population size of antigen-specific CD8 + T cells. (rupress.org)
  • An mAb to human CTLA-4 (ipilimumab, Bristol-Myers Squibb, BMS) has been found in clinical trials to elicit objective responses in cancer patients ( 10-13 ). (aacrjournals.org)
  • The first role of CTLA-4 in inhibiting T cell responses seem to be directly via SHP-2 and PP2A dephosphorylation of TCR-proximal signalling proteins such as CD3 and LAT. (wikipedia.org)
  • Methods: The functional protein tyrosine phosphatase type 22 (PTPN22) SNP (R620W rs2476601, 1858C/T), and two CTLA-4 SNPs (rs5742909, -318C/T and rs231775, 49A/G) were analyzed in 140 patients with AAU and 92 healthy controls by sequence-specific primer -polymerase chain reaction (SSP-PCR). (elsevier.com)
  • To test these models and to determine antigenic peptide reactivity of naive T cells in the absence of CTLA-4, we have initiated studies using MHC class I or class II-restricted TCR transgenic CTLA-4 −/− mice. (pnas.org)
  • However, those studies compared CTLA-4 positive cells, which are predominantly regulatory cells and are at least partially activated, with CTLA-4 negative naive T cells. (wikipedia.org)
  • Genetic susceptibility to type 1 autoimmune hepatitis is indicated by a preponderance of female subjects and strong associations with human leukocyte antigens (HLA) DRB1*0301 and DRB1*0401. (nih.gov)
  • The CTLA-4 G allele is more common in patients with type 1 autoimmune hepatitis and may represent a second susceptibility allele. (nih.gov)
  • genetic susceptibility, immune mediated with loss of tolerance to self-antigen (pyruvate dehydrogenase complex), defective bicarbonate umbrella. (medscape.com)
  • Particular genotypes of the locus encoding the CTLA-4 glycoprotein have been associated with susceptibility to various autoimmune diseases. (semanticscholar.org)
  • In addition to that, it has been found, dendritic cell (DC) - Treg interaction causes sequestration of Fascin-1, an actin-bundling protein essential for immunological synapse formation, and skews Fascin-1-dependent actin polarization in antigen presenting DCs toward the T reg cell adhesion zone. (wikipedia.org)
  • Interestingly, young AND TCR + CTLA-4 −/− mice carrying a null mutation in the rag-1 gene remain healthy and the T cells maintain a naive phenotype until later in life. (pnas.org)
  • Based on the phenotype of the CTLA-4 −/− mice, we proposed ( 15 , 16 ) that CTLA-4 may provide an inhibitory signal that prevents CD4 + T cell activation during the continuous interaction of TCR and MHC that is shown to be required for T cell survival ( 17 - 21 ). (pnas.org)
  • The CD8 + TCR transgenic CTLA-4 −/− T cells maintain a naive phenotype in these animals ( 23 , 24 ). (pnas.org)
  • Conclusions: The data do not support an association between SNPs in PTPN22 and CTLA-4, genes regarded as genetic master switches of autoimmunity. (elsevier.com)
  • CTLA-4-deficient mice develop a fatal lymphoproliferative disorder, characterized by polyclonal expansion of peripheral lymphocytes. (pnas.org)
  • The expression of the AND TCR transgene by CD4 + T cells delays but does not prevent the lymphoproliferation in the CTLA-4 −/− mice. (pnas.org)
  • CTLA-4-deficient mice die at 3-4 weeks of age as a result of a lymphoproliferative disorder caused by polyclonal T cell expansion ( 12 - 14 ). (pnas.org)
  • Peripheral CD4 + T cells are primarily responsible for the lymphoproliferative disorder in CTLA-4 −/− mice expressing an unmanipulated TCR repertoire ( 15 ). (pnas.org)
  • Mice depleted of CD8 + T cells from birth by antibody treatment develop a lymphoproliferative disorder similar in onset and severity to unmanipulated CTLA-4 −/− mice, whereas lymphoproliferation does not occur in CTLA-4 −/− mice depleted of CD4 + T cells from birth. (pnas.org)
  • CTLA-4 −/− mice expressing MHC class I-restricted TCR transgenes remain healthy for several months but eventually develop a lymphoproliferative disorder, apparently initiated by activation of the normally small population of CD4 + T cells present in these animals ( 22 , 23 ). (pnas.org)
  • C57BL/6 mice were inoculated i.p. with 1,000 Nb L3 larvae and treated with control hamster IgG (open squares) or hamster anti-mouse CTLA-4 mAb (filled squares) at 1 mg/week beginning at day 0. (nih.gov)
  • Values represent the mean concentration of IL-5 produced from 1 × 106 cells from 4 mice and adjusted to IL-5 production per lymph node based on the total lymph node cell number. (nih.gov)
  • We found that anti-CTLA-4 mAb treatment induced a profound 20-fold increase in IL-5 production (Fig. 1 a) and a massive 40-fold increase in IL-4 production (Fig. 2 a) from the draining mediastinal lymph node at day 6 after infection compared to mice given control antibody. (nih.gov)
  • The mediastinal lymph node obtained from mice given anti-CTLA-4 mAb had nearly fourfold more lymphocytes 6 d after infection than control mice (Fig. 3). (nih.gov)
  • In November 1995, the labs of Tak Wah Mak and Arlene H. Sharpe independently published their findings on the discovery of the function of CTLA-4 as a negative regulator of T-cell activation, by knocking out the gene in mice. (wikipedia.org)
  • The role of CTLA-4 in regulating homeostasis and antigen reactivity of CD8 + T cells has been examined in three different MHC class I-restricted TCR transgenic mouse strains ( 21 - 23 ). (pnas.org)
  • rather, accumulating evidence indicates that CTLA-4 may directly modulate proximal TCR signaling ( 5 - 11 ). (pnas.org)
  • In this study we have analyzed SNPs in PTPN22 and CTLA-4 in patients with AAU. (elsevier.com)
  • Our findings establish that the ICOS/ICOSL pathway is necessary for the optimal therapeutic effect of anti-CTLA-4, thus implicating this pathway as a target for future combinatorial strategies to improve the efficacy of anti-CTLA-4 therapy. (aacrjournals.org)
  • Treatment with anti-CTLA-4 greatly enhances IL-5 production in lymph nodes draining the sites of infection with Nb. (nih.gov)
  • After boost immunization with peptide or DNA, this effect was particularly profound, and antigen-specific CD8 + T cell populations were enlarged at least 10-fold. (rupress.org)
  • Here, we demonstrate cycling of CTLA-4 between intracellular stores and the cell surface. (nih.gov)
  • Promoter region -318 C/ T and -1661 A/G CTLA-4 single nucleotide polymorphisms and type 1 diabetes in North Indians. (cdc.gov)