Clonal Deletion: Removal, via CELL DEATH, of immature lymphocytes that interact with antigens during maturation. For T-lymphocytes this occurs in the thymus and ensures that mature T-lymphocytes are self tolerant. B-lymphocytes may also undergo clonal deletion.Minor Lymphocyte Stimulatory Antigens: Endogenous superantigens responsible for inducing strong proliferative responses in T-cells in mixed lymphocyte reactions (see LYMPHOCYTE CULTURE TEST, MIXED). They are encoded by mouse mammary tumor viruses that have integrated into the germ line as DNA proviruses (MINOR LYMPHOCYTE STIMULATORY LOCI).Gene Deletion: A genetic rearrangement through loss of segments of DNA or RNA, bringing sequences which are normally separated into close proximity. This deletion may be detected using cytogenetic techniques and can also be inferred from the phenotype, indicating a deletion at one specific locus.Thymus Gland: A single, unpaired primary lymphoid organ situated in the MEDIASTINUM, extending superiorly into the neck to the lower edge of the THYROID GLAND and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat.Sequence Deletion: Deletion of sequences of nucleic acids from the genetic material of an individual.Chromosome Deletion: Actual loss of portion of a chromosome.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.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.Mice, Transgenic: Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN.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.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)Self Tolerance: The normal lack of the ability to produce an immunological response to autologous (self) antigens. A breakdown of self tolerance leads to autoimmune diseases. The ability to recognize the difference between self and non-self is the prime function of the immune system.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.Nuclear Receptor Subfamily 4, Group A, Member 1: An orphan nuclear receptor that is closely related to members of the thyroid-steroid receptor gene family. It was originally identified in NERVE CELLS and may play a role in mediation of NERVE GROWTH FACTOR-induced CELL DIFFERENTIATION. However, several other functions have been attributed to this protein including the positive and negative regulation of APOPTOSIS.Clonal Anergy: Functional inactivation of T- or B-lymphocytes rendering them incapable of eliciting an immune response to antigen. This occurs through different mechanisms in the two kinds of lymphocytes and can contribute to SELF TOLERANCE.Thymocytes: HEMATOPOIETIC PROGENITOR CELLS that have migrated to the THYMUS where they differentiate into T-LYMPHOCYTES. Thymocytes are classified into maturational stages based on the expression of CELL SURFACE ANTIGENS.Mice, Inbred C57BLAntigens, 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.Autoantigens: Endogenous tissue constituents that have the ability to interact with AUTOANTIBODIES and cause an immune response.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.H-2 Antigens: The major group of transplantation antigens in the mouse.Superantigens: Microbial antigens that have in common an extremely potent activating effect on T-cells that bear a specific variable region. Superantigens cross-link the variable region with class II MHC proteins regardless of the peptide binding in the T-cell receptor's pocket. The result is a transient expansion and subsequent death and anergy of the T-cells with the appropriate variable regions.Mice, Inbred AKRMolecular 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.Base Sequence: The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by AUTOIMMUNE DISEASES.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.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.Radiation Chimera: An organism whose body contains cell populations of different genotypes as a result of the TRANSPLANTATION of donor cells after sufficient ionizing radiation to destroy the mature recipient's cells which would otherwise reject the donor 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.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.Mice, Inbred BALB CT-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.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.Lymphocyte Depletion: Immunosuppression by reduction of circulating lymphocytes or by T-cell depletion of bone marrow. The former may be accomplished in vivo by thoracic duct drainage or administration of antilymphocyte serum. The latter is performed ex vivo on bone marrow before its transplantation.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.Spleen: An encapsulated lymphatic organ through which venous blood filters.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.Mice, Inbred CBAMice, Knockout: Strains of mice in which certain GENES of their GENOMES have been disrupted, or "knocked-out". To produce knockouts, using RECOMBINANT DNA technology, the normal DNA sequence of the gene being studied is altered to prevent synthesis of a normal gene product. Cloned cells in which this DNA alteration is successful are then injected into mouse EMBRYOS to produce chimeric mice. The chimeric mice are then bred to yield a strain in which all the cells of the mouse contain the disrupted gene. Knockout mice are used as EXPERIMENTAL ANIMAL MODELS for diseases (DISEASE MODELS, ANIMAL) and to clarify the functions of the genes.Gene Rearrangement, beta-Chain T-Cell Antigen Receptor: Ordered rearrangement of T-cell variable gene regions coding for the beta-chain of antigen receptors.Chimera: An individual that contains cell populations derived from different zygotes.Mice, Inbred C3HFlow 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.Apoptosis: One of the mechanisms by which CELL DEATH occurs (compare with NECROSIS and AUTOPHAGOCYTOSIS). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA; (DNA FRAGMENTATION); at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth.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.Mutation: Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.CD4-CD8 Ratio: Ratio of T-LYMPHOCYTES that express the CD4 ANTIGEN to those that express the CD8 ANTIGEN. This value is commonly assessed in the diagnosis and staging of diseases affecting the IMMUNE SYSTEM including HIV INFECTIONS.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.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.Ovalbumin: An albumin obtained from the white of eggs. It is a member of the serpin superfamily.Animals, Newborn: Refers to animals in the period of time just after birth.Mammary Tumor Virus, Mouse: The type species of BETARETROVIRUS commonly latent in mice. It causes mammary adenocarcinoma in a genetically susceptible strain of mice when the appropriate hormonal influences operate.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.Interleukin-2: A soluble substance elaborated by antigen- or mitogen-stimulated T-LYMPHOCYTES which induces DNA synthesis in naive lymphocytes.Antigen Presentation: The process by which antigen is presented to lymphocytes in a form they can recognize. This is performed by antigen presenting cells (APCs). Some antigens require processing before they can be recognized. Antigen processing consists of ingestion and partial digestion of the antigen by the APC, followed by presentation of fragments on the cell surface. (From Rosen et al., Dictionary of Immunology, 1989)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, 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.Enterotoxins: Substances that are toxic to the intestinal tract causing vomiting, diarrhea, etc.; most common enterotoxins are produced by bacteria.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.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.Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs.Antigens: Substances that are recognized by the immune system and induce an immune reaction.Receptors, Steroid: Proteins found usually in the cytoplasm or nucleus that specifically bind steroid hormones and trigger changes influencing the behavior of cells. The steroid receptor-steroid hormone complex regulates the transcription of specific genes.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.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, Monoclonal: Antibodies produced by a single clone of cells.Bone Marrow Cells: Cells contained in the bone marrow including fat cells (see ADIPOCYTES); STROMAL CELLS; MEGAKARYOCYTES; and the immediate precursors of most blood cells.Signal Transduction: The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.Lymph Nodes: They are oval or bean shaped bodies (1 - 30 mm in diameter) located along the lymphatic system.Receptors, Interleukin-2: Receptors present on activated T-LYMPHOCYTES and B-LYMPHOCYTES that are specific for INTERLEUKIN-2 and play an important role in LYMPHOCYTE ACTIVATION. They are heterotrimeric proteins consisting of the INTERLEUKIN-2 RECEPTOR ALPHA SUBUNIT, the INTERLEUKIN-2 RECEPTOR BETA SUBUNIT, and the INTERLEUKIN RECEPTOR COMMON GAMMA-CHAIN.Bone Marrow Transplantation: The transference of BONE MARROW from one human or animal to another for a variety of purposes including HEMATOPOIETIC STEM CELL TRANSPLANTATION or MESENCHYMAL STEM CELL TRANSPLANTATION.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.Phenotype: The outward appearance of the individual. It is the product of interactions between genes, and between the GENOTYPE and the environment.Hematopoietic Stem Cells: Progenitor cells from which all blood cells derive.Chromosome Mapping: Any method used for determining the location of and relative distances between genes on a chromosome.DNA Mutational Analysis: Biochemical identification of mutational changes in a nucleotide sequence.Plasmids: Extrachromosomal, usually CIRCULAR DNA molecules that are self-replicating and transferable from one organism to another. They are found in a variety of bacterial, archaeal, fungal, algal, and plant species. They are used in GENETIC ENGINEERING as CLONING VECTORS.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.Exons: The parts of a transcript of a split GENE remaining after the INTRONS are removed. They are spliced together to become a MESSENGER RNA or other functional RNA.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.Promoter Regions, Genetic: DNA sequences which are recognized (directly or indirectly) and bound by a DNA-dependent RNA polymerase during the initiation of transcription. Highly conserved sequences within the promoter include the Pribnow box in bacteria and the TATA BOX in eukaryotes.Chromosomes, Human, Pair 22: A specific pair of GROUP G CHROMOSOMES of the human chromosome classification.Transcription, Genetic: The biosynthesis of RNA carried out on a template of DNA. The biosynthesis of DNA from an RNA template is called REVERSE TRANSCRIPTION.Cell Line: Established cell cultures that have the potential to propagate indefinitely.Escherichia coli: A species of gram-negative, facultatively anaerobic, rod-shaped bacteria (GRAM-NEGATIVE FACULTATIVELY ANAEROBIC RODS) commonly found in the lower part of the intestine of warm-blooded animals. It is usually nonpathogenic, but some strains are known to produce DIARRHEA and pyogenic infections. Pathogenic strains (virotypes) are classified by their specific pathogenic mechanisms such as toxins (ENTEROTOXIGENIC ESCHERICHIA COLI), etc.Mutagenesis: Process of generating a genetic MUTATION. It may occur spontaneously or be induced by MUTAGENS.DNA Primers: Short sequences (generally about 10 base pairs) of DNA that are complementary to sequences of messenger RNA and allow reverse transcriptases to start copying the adjacent sequences of mRNA. Primers are used extensively in genetic and molecular biology techniques.In Situ Hybridization, Fluorescence: A type of IN SITU HYBRIDIZATION in which target sequences are stained with fluorescent dye so their location and size can be determined using fluorescence microscopy. This staining is sufficiently distinct that the hybridization signal can be seen both in metaphase spreads and in interphase nuclei.Restriction Mapping: Use of restriction endonucleases to analyze and generate a physical map of genomes, genes, or other segments of DNA.Saccharomyces cerevisiae: A species of the genus SACCHAROMYCES, family Saccharomycetaceae, order Saccharomycetales, known as "baker's" or "brewer's" yeast. The dried form is used as a dietary supplement.Homozygote: An individual in which both alleles at a given locus are identical.22q11 Deletion Syndrome: Condition with a variable constellation of phenotypes due to deletion polymorphisms at chromosome location 22q11. It encompasses several syndromes with overlapping abnormalities including the DIGEORGE SYNDROME, VELOCARDIOFACIAL SYNDROME, and CONOTRUNCAL AMOMALY FACE SYNDROME. In addition, variable developmental problems and schizoid features are also associated with this syndrome. (From BMC Med Genet. 2009 Feb 25;10:16) Not all deletions at 22q11 result in the 22q11deletion syndrome.Recombination, Genetic: Production of new arrangements of DNA by various mechanisms such as assortment and segregation, CROSSING OVER; GENE CONVERSION; GENETIC TRANSFORMATION; GENETIC CONJUGATION; GENETIC TRANSDUCTION; or mixed infection of viruses.Bacterial Proteins: Proteins found in any species of bacterium.Abnormalities, MultipleAlleles: Variant forms of the same gene, occupying the same locus on homologous CHROMOSOMES, and governing the variants in production of the same gene product.DNA-Binding Proteins: Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases.Genetic Complementation Test: A test used to determine whether or not complementation (compensation in the form of dominance) will occur in a cell with a given mutant phenotype when another mutant genome, encoding the same mutant phenotype, is introduced into that cell.Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.Blotting, Southern: A method (first developed by E.M. Southern) for detection of DNA that has been electrophoretically separated and immobilized by blotting on nitrocellulose or other type of paper or nylon membrane followed by hybridization with labeled NUCLEIC ACID PROBES.

Cytotoxic T lymphocytes to an unmutated tumor rejection antigen P1A: normal development but restrained effector function in vivo. (1/361)

Unmutated tumor antigens are chosen as primary candidates for tumor vaccine because of their expression on multiple lineages of tumors. A critical issue is whether unmutated tumor antigens are expressed in normal cells, and if so, whether such expression imposes special restrictions on cytotoxic T lymphocyte (CTL) responses. In this study, we use a transgenic approach to study the development and effector function of T cells specific for P1A, a prototypical unmutated tumor antigen. We report here that although P1A is expressed at low levels in normal tissues, including lymphoid tissues, the P1A-specific transgenic T cells develop normally and remain highly responsive to the P1A antigen. The fact that transgenic expression of P1A antigen in the thymus induces T cell clonal deletion demonstrates that normal hematopoietic cells can process and present the P1A antigen and that P1A-specific T cells are susceptible to clonal deletion. By inference, P1A-specific T cells must have escaped clonal deletion due to low expression of P1A in the thymus. Interestingly, despite the fact that an overwhelming majority of T cells in the T cell receptor for antigen (TCR)-transgenic mice are specific for P1A, these mice are no more resistant to a P1A-expressing plasmocytoma than nontransgenic littermates. Moreover, when the same TCR-transgenic mice were challenged simultaneously with B7-1(+) and B7-1(-) tumors, only B7-1(+) tumors were rejected. Therefore, even though P1A can be a tumor rejection antigen, the effector function of P1A-specific CTL is restrained in vivo. These results have important implications for the strategy of tumor immunotherapy.  (+info)

Chimerism and xenotransplantation. New concepts. (2/361)

In both transplant and infectious circumstances, the immune response is governed by migration and localization of the antigen. If the antigenic epitopes of transgenic xenografts are sufficiently altered to avoid evoking the destructive force of innate immunity, the mechanisms of engraftment should be the same as those that permit the chimerism-dependent immunologic confrontation and resolution that is the basis of allograft acceptance. In addition to "humanizing" the epitopes, one of the unanswered questions is whether the species restriction of complement described in 1994 by Valdivia and colleagues also necessitates the introduction of human complement regulatory genes in animal donors. Because the liver is the principal or sole source of most complement components, the complement quickly is transformed to that of the donor after hepatic transplantation. Thus, the need for complementary regulatory transgenes may vary according to the kind of xenograft used. Much evidence shows that physiologically important peptides produced by xenografts (e.g., insulin, clotting factors, and enzymes) are incorporated into the metabolic machinery of the recipient body. To the extent that this is not true, xenotransplantation could result in the production of diseases that are analogous to inborn errors of metabolism. In the climate of pessimism that followed the failures of baboon to human liver xenotransplantation in 1992-1993, it seemed inconceivable that the use of even more discordant donors, such as the pig, could ever be seriously entertained; however, this preceded insight into the xenogeneic and allogeneic barriers that has brought transplantation infectious immunity to common ground. With this new insight and the increasing ease of producing transgenic donors, the goal of clinical xenotransplantation may not be so distant.  (+info)

Cutting edge: negative selection of immature thymocytes by a few peptide-MHC complexes: differential sensitivity of immature and mature T cells. (3/361)

We quantitated the number of peptide-class II MHC complexes required to affect the deletion or activation of 3A9 TCR transgenic thymocytes. Deletion of immature double positive thymocytes was very sensitive, taking place with approximately three peptide-MHC complexes per APC. However, the activation of mature CD4+ thymocytes required 100-fold more complexes per APC. Therefore, a "biochemical margin of safety" exists at the level of the APC. To be activated, autoreactive T cells in peripheral lymphoid tissues require a relatively high level of peptide-MHC complexes.  (+info)

Chronic modulation of the TCR repertoire in the lymphoid periphery. (4/361)

Using TCR V beta 5 transgenic mice as a model system, we demonstrate that the induction of peripheral tolerance can mold the TCR repertoire throughout adult life. In these mice, three distinct populations of peripheral T cells are affected by chronic selective events in the lymphoid periphery. First, CD4+V beta 5+ T cells are deleted in the lymphoid periphery by superantigens encoded by mouse mammary tumor viruses-8 and -9 in an MHC class II-dependent manner. Second, mature CD8+V beta 5+ T cells transit through a CD8lowV beta 5low deletional intermediate during tolerance induction by a process that depends upon neither mouse mammary tumor virus-encoded superantigens nor MHC class II expression. Third, a population of CD4-CD8-V beta 5+ T cells arises in the lymphoid periphery in an age-dependent manner. We analyzed the TCR V alpha repertoire of each of these cellular compartments in both V beta 5 transgenic and nontransgenic C57BL/6 mice as a function of age. This analysis revealed age-related changes in the expression of V alpha families among different cellular compartments, highlighting the dynamic state of the peripheral immune repertoire. Our work indicates that the chronic processes maintaining peripheral T cell tolerance can dramatically shape the available TCR repertoire.  (+info)

Survival of naive CD4 T cells: roles of restricting versus selecting MHC class II and cytokine milieu. (5/361)

The diversity of naive CD4 T cells plays an important role in the adaptive immune response by ensuring the capability of responding to novel pathogens. In the past, it has been generally accepted that naive CD4 T cells are intrinsically long-lived; however, there have been studies suggesting some CD4 T cells are short-lived. In this report, we identify two populations of naive CD4 T cells: a long-lived population as well as a short-lived population. In addition, we identify two factors that contribute to the establishment of long-lived naive CD4 T cells. We confirm earlier findings that MHC class II interaction with the TCR on CD4 T cells is important for survival. Furthermore, we find that MHC class II alleles with the correct restriction element for Ag presentation mediate the peripheral survival of naive CD4 T cells more efficiently than other positively selecting alleles, regardless of the selecting MHC in the thymus. The second component contributing to the survival of naive CD4 T cells is contact with the cytokines IL-4 and IL-7. We find that the physiological levels of IL-4 and IL-7 serve to enhance the MHC class II-mediated survival of naive CD4 T cells in vivo.  (+info)

Two mechanisms for the non-MHC-linked resistance to spontaneous autoimmunity. (6/361)

Genetic susceptibility and resistance to most autoimmune disorders are associated with highly polymorphic genes of the MHC and with non-MHC-linked polygenic modifiers. It is known that non-MHC-linked polymorphisms can override or enhance the susceptibility to an autoimmune disease provided by pathogenic MHC genes, but the mechanisms remain elusive. In this study, we have followed the fate of two highly diabetogenic beta cell-specific T cell receptors (Kd and I-Ag7 restricted, respectively) in NOR/Lt mice, which are resistant to autoimmune diabetes despite expressing two copies of the diabetogenic MHC haplotype H-2g7. We show that at least two mechanisms of non-MHC-linked control of pathogenic T cells operate in these mice. One segregates as a recessive trait and is associated with a reduction in the peripheral frequency of diabetogenic CD8+ (but not CD4+) T cells. The other segregates as a dominant trait and is mediated by IL-4- and TGF-beta1-independent immune suppressive functions provided by lymphocytes that target diabetogenic CD4+ and CD8+ T cells, without causing their deletion, anergy, immune deviation, or ignorance. These results provide explanations as to how non-MHC-linked polymorphisms can override the susceptibility to an autoimmune disease provided by pathogenic MHC haplotypes, and demonstrate that protective non-MHC-linked genes may selectively target specific lymphoid cell types in cellularly complex autoimmune responses.  (+info)

Autoantigen-independent deletion of diabetogenic CD4+ thymocytes by protective MHC class II molecules. (7/361)

Some MHC class II genes provide dominant resistance to certain autoimmune diseases via mechanisms that remain unclear. We have shown that thymocytes bearing a highly diabetogenic, I-Ag7-restricted beta-cell-reactive TCR (4.1-TCR) undergo negative selection in diabetes-resistant H-2g7/x mice by engaging several different antidiabetogenic MHC class II molecules on thymic (but not peripheral) hemopoietic cells, independently of endogenous superantigens. Here we have investigated 1) whether this TCR can also engage protective MHC class II molecules (I-Ab) on cortical thymic epithelial cells in the absence of diabetogenic (I-Ag7) molecules, and 2) whether deletion of 4.1-CD4+ thymocytes in I-Ab-expressing mice might result from the ability of I-Ab molecules to present the target beta-cell autoantigen of the 4.1-TCR. We show that, unlike I-Ag7 molecules, I-Ab molecules can restrict neither the positive selection of 4.1-CD4+ thymocytes in the thymic cortex nor the presentation of their target autoantigen in the periphery. Deletion of 4.1-CD4+ thymocytes by I-Ab molecules in the thymic medulla, however, is a peptide-specific process, since it can be triggered by hemopoietic cells expressing heterogeneous peptide/I-Ab complexes, but not by hemopoietic cells expressing single peptide/I-Ab complexes. Thus, unlike MHC-autoreactive or alloreactive TCRs, which can engage deleting MHC molecules in the thymic cortex, thymic medulla, and peripheral APCs, the 4.1-TCR can only engage deleting MHC molecules (I-Ab) in the thymic medulla. We therefore conclude that this form of MHC-induced protection from diabetes is based on the presentation of an anatomically restricted, nonautoantigenic peptide to highly diabetogenic thymocytes.  (+info)

Negative selection of immature B cells by receptor editing or deletion is determined by site of antigen encounter. (8/361)

Immature B cells that encounter self-antigen are eliminated from the immune repertoire by negative selection. Negative selection has been proposed to take place by two distinct mechanisms: deletion by apoptosis or alteration of the antigen receptor specificity by receptor editing. While convincing evidence exists for each, the two models are inherently contradictory. In this paper, we propose a resolution to this contradiction by demonstrating that the site of first antigen encounter dictates which mechanism of negative selection is utilized. We demonstrate that the bone marrow microenvironment provides signals that block antigen-induced deletion and promote RAG reinduction. In the periphery, the absence of these signals allows the immature B cell to default to apoptosis as a result of BCR engagement.  (+info)

Looking for online definition of clonal deletion theory in the Medical Dictionary? clonal deletion theory explanation free. What is clonal deletion theory? Meaning of clonal deletion theory medical term. What does clonal deletion theory mean?
In this work, we have shown that overexpression of Bcl-2 protects peripheral CD8 T cells from deletion in response to cross-presented self antigen. The OT-I.Eμ-Bcl-2 and OT-I.vav.Bcl-2 cells appeared similar to wild-type OT-I cells in their ability to be activated and proliferate in response to cross-presented self-antigen. If sufficiently high numbers of OT-I.Eμ-Bcl-2 T cells were transferred, they induced autoimmune diabetes (Table I). As a pro-survival molecule Bcl-2 protects lymphocytes in vitro and in vivo against apoptosis induced by growth factor deprivation, DNA damage or treatment with corticosteroids or calcium ionophores (16). For activated T cells in vivo, bcl-2 transgene expression prolongs T cell survival following injection of mice with the superantigen staphylococcus enterotoxin B (SEB; reference 16), the transfer of HY-TCR CD8 T cells into male recipients (18), the immunization of mice expressing a transgenic LCMV-TCR in CD8 T cells with LCMV peptide (19) and the immunization ...
The developmental pathway that TCRαβ+CD8αα+ intestinal intraepithelial lymphocytes (here called unconventional iIEL) follow has long remained a mystery. In their recent paper, McDonald et al. cloned and forced the expression of TCRs isolated from unconventional iIEL and came to the following conclusions. First, TCR specificity drives commitment to the unconventional iIEL lineage. Second, iIEL TCRs induce a pattern of thymic negative selection, with most cells expressing these TCR undergoing apoptosis but a small proportion of them escaping deletion and selectively maturing into unconventional iIEL. Third, the post-selection precursors to unconventional iIEL are the CD4loCD8lo(DPlo)CD69hiPD-1hi thymocytes, a population that largely overlaps with the general pool of MHC class I- or MHC class II-autoreactive thymocytes that undergo negative selection. By downregulating the expression of both CD4 and CD8b coreceptors, these cells largely lose their ability to recognize self ligands and, instead ...
There is clear evidence that tumor patients are able to generate TAA-specific T cell immunity spontaneously. Whereas the presence of tumor-specific T cells has been shown by many groups and for various tumor types, much less is known about the function of TAA-specific T cells in vivo. Most of the TAAs including differentiation, germ-line, and shared overexpressed antigens are not tumor specific but are also expressed at low levels in certain nonmalignant tissues. This should influence the type of T cell response because deletion of functional high-avidity self-reactive T cells in the thymus as well as peripheral deletion or anergy was shown in various animal models (reviewed in Ref. 74 ). There are a few recent studies analyzing the functional avidity of TAA-specific T cells in patients. In leukemia patients, low-avidity T cells to proteinase 3, which are able to kill leukemia cells, can readily be expanded. However, high-avidity T cells can also be expanded from patients in cytogenetic ...
Studies using the 4.1 TCR transgenic system found thymic or peripheral deletion as well as anergy and ignorance do not contribute to CD4 T-cell tolerance induction in NOR mice (13). Similarly, we found the frequency and proliferative capacity of BDC2.5-like CD4 T-cells was comparable in NOD and NOR mice. The fact that NOR CD4 T-cells induced type 1 diabetes in some NOD.CD4null recipients revealed the retention of at least minimal pathogenic activity. On the other hand, NOR T-cells are more susceptible than those from NOD mice to activation-induced cell death (AICD) (34). Therefore, abortive activation followed by AICD may limit the effector function of NOR diabetogenic CD4 T-cells. Another nonmutually exclusive possibility is that diabetogenic CD4 T-cells are more efficiently suppressed in NOR than NOD mice. However, we found no difference in the frequency or in vitro suppressive function between NOD and NOR Tregs. These results suggested that Treg function and the sensitivity of effector ...
Plant-based diets may be protective against multiple sclerosis because IGF-1 can prevent our immune system from eliminating autoimmune cells.
Non- H-2 genes responsible for negative selection of Tcrb-V 11+ T cells were examined using backcross mice of various strains with C58, which does not delete Tcrb-V 11+ T cells. Two independently segr
The findings here demonstrate that selectively restoring B7.2 expression on otherwise self-tolerant B cells is sufficient to switch their fate from peripheral deletion to large-scale proliferation and autoantibody secretion during interactions with specific CD4+ T cells. Of the many early signals and responses to BCR engagement that are repressed or altered in tolerant B cells ((12)-(14)), the data here single out repression of the B7.2 response as being necessary to allow peripheral tolerance by FasL/Fas-mediated clonal abortion. The findings raise interesting questions about how B7.2 switches the outcome of interactions between tolerant B and T cells, and highlight the regulation of B7.2 in B cells as a key process that may be dysregulated by inherited or acquired triggers to systemic autoimmune disease.. Three possible mechanisms may in principle explain how dysregulated expression of B7.2 on tolerant B cells switches the outcome of interactions with autoantigen-specific T cells from deletion ...
CD30 is a type I transmembrane glycoprotein of the TNF receptor superfamily. CD30 was originally identified as a cell surface antigen of Hodgkins and Reed-Sternberg cells using monoclonal antibody Ki-1. The ligand for CD30 is CD30L (CD153). The binding of CD30 to CD30L mediates pleiotropic effects including cell proliferation, activation, differentiation, and apoptotic cell death. CD30 has a critical role in the pathophysiology of Hodgkins disease and other CD30+ lymphomas. CD30 acts as a costimulatory molecule in thymic negative selection. In addition to its expression on Hodgkins and Reed-Sternberg cells, CD30 is also found in some non-Hodgkins lymphomas (including Burkitts lymphomas), virus-infected T and B cells, and on normal T and B cells after activation. In T cells, CD30 expression is present on a subset of T cells that produce Th2-type cytokines and on CD4+/CD8+ thymocytes that co-express CD45RO and the IL4 receptor. Soluble form of CD30 (sCD30) serves as a marker reflecting Th2 ...
CD4+ Foxp3+ regulatory T (Treg) cells belong to a distinct T cell lineage which develops in the thymus and is essential for the prevention of self-reactivity by suppressing peripheral auto-reactive T cells that escape thymic negative selection. IL-2/IL-2R signaling is crucial and non-redundant for the development of thymic Treg cells, as well as the homeostasis and competitive fitness of peripheral Treg cells. The central role of IL-2 in Treg biology is exemplified by the uncontrolled massive lymphoproliferation associated with IL-2-/-, IL-2Rα-/- and IL-2Rβ-/- mice which typically die by 4-12 week of age. It is noteworthy that a restored normal percentage and number of peripheral Treg cells in Bim-/- IL-2-/- mice did not rescue these mice from severe autoimmunity. Instead, additional IL-2 was still required for the proper functioning of peripheral Bim-/- IL-2-/- Treg cells. Consistently, in the current studies, we found that the development of thymic Treg cells was blocked with mostly CD4+ CD25-
Clonal deletion of autoreactive T cells in the thymus is not the sole mechanism for the induction of tolerance to self-antigens since partial depletion of peripheral CD4(+) T cells from neonatal and adult animals results in the development of organ-specific autoimmunity. Reconstitution of these immu …
EasySep™ is a fast, easy and column-free cell separation platform that allows you to separate highly purified cells in as little as 8 minutes. This video will take you through the isolation of human CD4+ T cells by negative selection using EasySep™.
The cell surface receptor Fas (FasR, Apo-1, CD95) and its ligand (FasL) are mediators of apoptosis that have been shown to be implicated in the peripheral deletion of autoimmune cells, activation-induced T cell death, and one of the two major cytolytic pathways mediated by CD8+ cytolytic T cells. To gain further understanding of the Fas system., we have analyzed Fas and FasL expression during mouse development and in adult tissues. In developing mouse embryos, from 16.5 d onwards, Fas mRNA is detectable in distinct cell types of the developing sinus, thymus, lung, and liver, whereas FasL expression is restricted to submaxillary gland epithelial cells and the developing nervous system. Significant Fas and FasL expression were observed in several nonlymphoid cell types during embryogenesis, and generally Fas and FasL expression were not localized to characteristic sites of programmed cell death. In the adult mouse, RNase protection analysis revealed very wide expression of both Fas and FasL. ...
The cell surface receptor Fas (FasR, Apo-1, CD95) and its ligand (FasL) are mediators of apoptosis that have been shown to be implicated in the peripheral deletion of autoimmune cells, activation-induced T cell death, and one of the two major cytolytic pathways mediated by CD8+ cytolytic T cells. To gain further understanding of the Fas system., we have analyzed Fas and FasL expression during mouse development and in adult tissues. In developing mouse embryos, from 16.5 d onwards, Fas mRNA is detectable in distinct cell types of the developing sinus, thymus, lung, and liver, whereas FasL expression is restricted to submaxillary gland epithelial cells and the developing nervous system. Significant Fas and FasL expression were observed in several nonlymphoid cell types during embryogenesis, and generally Fas and FasL expression were not localized to characteristic sites of programmed cell death. In the adult mouse, RNase protection analysis revealed very wide expression of both Fas and FasL. ...
Dear Immunonetters, I would like to bring another player into the Self/non-self discrimination arena. That Being the effect of Anergic T-cells on other autoreactive T-cells.This concept has been discussed in the papers by Lasalle and Hafler ( FASEB J. 8:601-608 1994) and Lombardi et al ( science 264:1587 1994). I agree with the authors that the Anergic T-cells play an important rolein self/nonself discrimination. In summary this is whats happening. The Thymus, site of clonal deletion, is very efficient in removing autoreactive T-cells. But nothing is perfect and some autoreactive cells escape this screening. These T-cells can be safely present in the periphery if the antigens they are reactive to are hidden away from them or not presented to them. This is called Clonal Ignorance. If MHC/AG is presented to the autoreactive T-cell but is not followed by costimulation, the result is Clonal anergy. In these cases the T-cells can recognize the self antigen however the extent of the response stops ...
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Dendritic cells (DCs) are known to regulate immune responses by inducing both central and peripheral tolerance. DCs play a vital role in negative selection of developing thymocytes by deleting T cells with high-affinity for self-peptide-major histocompatibility complexes. In the periphery, DCs mediate peripheral tolerance by promoting regulatory T-cell development, induction of T-cell unresponsiveness, and deletion of activated T cells. We studied whether allogeneic DCs, obtained from bone marrow cultured with either Flt3L (FLDCs) or granulocyte-macrophage colony-stimulating factor (GMDCs), could induce allospecific central and peripheral tolerance after IV injection; B cells were used as a control. The results showed that only FLDCs reached the thymus after injection and that these cells induced both central and peripheral tolerance to donor major histocompatibility complexes. For central tolerance, injection of FLDCs induced antigen-specific clonal deletion of both CD8 and CD4 single-positive
An amphetamine tolerance can cause a person to take more amphetamines than they really need, and can cause their body to become dependent then addicted.
In a healthy individual, the immune system uses several different immune tolerance mechanisms in order to prevent the development of autoimmune disease. For T c...
If your not confident, buythe parts and bring it to Leeds, I will do it for you. It would be most of the day. If not here goes. 1) you have to be sure thats the problem. 2) How many hours has the
In this project we propose to determine the role of candidate G protein-coupled receptors (GPCRs) in enforcing deletion of developing auto-reactive T cells in t...
Deletion of autoreactive thymocytes at the DP stage is the basis for tolerance to thymus-expressed self antigens. In this study we investigated whether distinct signalling pathways are induced in DP thymocytes as compared to mature T cells upon stimulation with antigen. Using triple transgenic mice expressing a TCR transgene, dominant negative ras/Mek proteins and a reporter gene construct with AP-1 or NF-kappa B binding sites, we showed a complete lack of transcriptional activity of NF-kappa B but not AP-1 in DP thymocytes, whereas both were transcriptionally active in mature T cells after antigenic stimulation. Lack of NF-kappa B induction correlated with increased death in response to antigen. AP-1 induction was dependent on the integrity of the ras/Mek pathway indicating that this pathway was activated in the DP thymocytes. In contrast, we found a complete lack of constitutive expression of the epsilon isoform of Protein Kinase C (PKC) in DP thymocytes, although it was present in mature thymocytes
Mentor: Nina Luning Prak, MD, PhD, University of Pennsylvania School of Medicine. Aberrant light chain rearrangement has been implicated in the loss of tolerance in self-reactive B cells. Ongoing light chain rearrangement, a process termed receptor editing, is a major mechanism for tolerizing self-reactive B cells. We have observed that highly edited B cells become less frequent once fully assembled antibody molecules are expressed on the B cell surface. We hypothesized that the decrease in highly edited B cells is due either to negative selection (death of cells that have failed to edit successfully), positive selection of cells with fewer rearrangements or escape of edited B cells to a hitherto unidentified peripheral compartment. Here, we report preliminary data from a pilot experiment that macrophages may be involved in the selective depletion of highly edited B cells. Flow cytometry analysis revealed co-expression of macrophage markers, F4/8 and CD-11, in anti-DNA heavy chain knock-in mouse ...
Figure 10. Killer T-cells eliminate intracellular pathogens. Intracellular pathogens are eliminated by a specialized type of lymphocyte, called a killer T-cell (see figure 10. Killer T-cells are a subclass of T-cells, meaning that they mature in the thymus, are tolerized via clonal deletion, and do not hypermutate when cloning. Killer T-cells bind not to simple proteins, but to proteins held by MHC molecules. In other words, killer T-cells can only recognize proteins expressed by MHC on the surface of host cells. If a killer T-cell is activated by recognition of a MHC/protein combination, it will kill the infected host cell. There are many ways in which this is done, e.g. killer T-cells can punch holes in cell walls, or secrete chemicals that destroy cell walls, etc. NEXT: Summary ...
Here are some very clear clips for the immune responses to infection, starting with a really well done explanation of Burnets Nobel-winning clonal selection theory: If you like that, check out some more of the videos from the Walter and Eliza Hall Institute of Medical Research. Try this animation and quiz: McGraw Hill Online Centre…
A clonal chromosome deletion 2p21 was found in endomyometriosis by Verhest et al. while Pai evidenced a strict relationship ... Verhest A, Simonart T, Noel JC (1996). A unique clonal chromosome 2 deletion in endomyometriosis. Cancer Genet Cytogenet 1996; ...
"Intrathymic and extrathymic clonal deletion of T cells." Current opinion in immunology 7.2 (1995): 196-205. Crotty, Shane, et ... The memory B cell has already undergone clonal expansion and differentiation and affinity maturation, so it is able to divide ...
... costimulation promotes maturation of regulatory T cell precursors and prevents their clonal deletion. „Front Immunol". 2, s. 30 ...
2008). "Autoreactive T cells escape clonal deletion in the thymus by a CD24-dependent pathway". J. Immunol. 181 (1): 320-8. doi ...
Most T cells are, in time, eliminated in the thymus by a process of clonal deletion. However, some of them escape this process ...
Just as in T cells, clonal deletion and clonal anergy can physically eliminate autoreactive B cell clones. Receptor editing is ... This negative selection is known as clonal deletion, one of the mechanisms for B cell tolerance. Approximately 0.99 percent of ... The mechanism of clonal anergy is important to maintain tolerance to many autologous antigens. Active suppression is the other ... This same positive and negative selection mechanism, but in peripheral tissues, is known as clonal anergy. ...
This clonal deletion of T cells in the thymus cannot eliminate every potentially self-reactive T cell; T cells that recognize ... This antigen induced loss of cells from the B cell repertoire is known as clonal deletion. B cells may encounter two types of ... they are eliminated by a process known as clonal deletion. These B cells are believed to undergo programmed cell death or ...
Both activated T cells and B cells express Fas and undergo clonal deletion by the AICD mechanism. Activated T cells that ...
This can induce T cell clonal deletion, T cell anergy or the proliferation of regulatory T cells (Tregs). Collectively, these ...
Clonal Deletion theory, proposed by Burnet, according to which self-reactive lymphoid cells are destroyed during the ... Clonal Anergy theory, proposed by Nossal, in which self-reactive T- or B-cells become inactivated in the normal individual and ... Clonal Ignorance theory, according to which autoreactive T cells that are not represented in the thymus will mature and migrate ... Consequently, auto-reactive B cells, that escape deletion, cannot find the antigen or the specific helper T cell.[8] ...
In either case, the B cell is allowed to proliferate or is killed off through a process called clonal deletion. Normally, the ...
... pivotal role of intrathymic clonal deletion and thymic dependence of bone marrow microchimerism-associated tolerance". ...
Nature 333, 742-746 (1988); Swat, W., Ignatowicz, L., von Boehmer, H. and Kisielow, P.: Clonal deletion of immature CD4+8+ ... Nature 351, 150 (1991). Central tolerance by deletion of immature T cells in TCR transgenic mice. Teho H. S., Kisielow, P., ... Science 251, 1225 (1991). Peripheral tolerance by deletion of and reversible anergy in matureT cells. Borgulya, P., Kishi, H., ...
Mechanisms of peripheral tolerance include direct inactivation of effector T cells by either clonal deletion, conversion to ...
... evidence against clonal deletion as the mechanism of tolerance induction". Scandinavian Journal of Immunology. 8 (1): 29-37. ...
... clonal deletion, receptor editing, anergy, or ignorance (B cell ignores signal and continues development). This negative ...
... who were the first to propose the deletion of self-reactive lymphocytes to establish tolerance, now termed clonal deletion. ... The deletion threshold is much more stringent for T cells than for B cells since T cells alone can cause direct tissue damage. ...
... clonal anergy, deletion, and ignorance. While autoimmunity is thought to result from the breakdown of central and peripheral ... This mutant form of the anti-CD3 acts by only delivering a partial signal to the T-cell, leading to inactivation, deletion, and ... although a few T-cells will escape thymic deletion. However, these potentially self-reactive cells in the periphery are held in ...
... demonstrating that neither thymus nor clonal deletion is necessary to induce tolerance. In 1989 was successfully induced ...
... clonal anergy MeSH G04.610.484.120 --- clonal deletion MeSH G04.610.484.800 --- self tolerance MeSH G04.610.484.910 --- ...
Three hypotheses have gained widespread attention among immunologists: Clonal Deletion theory, proposed by Burnet, according to ... Pike B, Boyd A, Nossal G (1982). "Clonal anergy: the universally anergic B lymphocyte". Proceedings of the National Academy of ... Consequently, auto-reactive B cells, that escape deletion, cannot find the antigen or the specific helper T cell. Suppressor ... In addition, two other theories are under intense investigation: Clonal Ignorance theory, according to which autoreactive T ...
Clonal anergy Clonal deletion Clonal selection Clone (cell biology) CMKLR1 Colony stimulating factor 1 receptor Colony- ...
Autoimmunity Alloimmunity Cross-reactivity Tolerance Central tolerance Peripheral tolerance Clonal anergy Clonal deletion ... Mimotope Tumor antigen Antigen-antibody interaction Immunogenetics Affinity maturation Somatic hypermutation Clonal selection V ...
Stimulation of mature T cells and clonal deletions in neonatal mice," Cell, v.56, n.1, pp. 27-35 (1989). 1986 - Appointed ... J.W. Kappler, M. Roehm, P. Marrack, "T cell tolerance by clonal elimination in the thymus," Cell, v.49, n.2, pp. 273-80 (1987) ...
... may refer to in Immunology Clonal deletion, a process by which B cells and T cells are deactivated before act ... significantly upon specific antigens Clonal selection theory, a model for how the immune system responds to infection Clonal ... also called clonal anemone Vegetative cloning, a form of asexual reproduction in plants Clone (disambiguation) Clonalis House ... anergy, a lack of reaction by the body's defense mechanisms to foreign substance in Biology Clonal interference, a phenomenon ...
Clonal anergy. *Clonal deletion. *Tolerance in pregnancy. *Immunodeficiency. Immunogenetics. *Affinity maturation *Somatic ...
Thus, clonal deletion can help protect individuals against autoimmunity. Clonal deletion is thought to be the most common type ... Incomplete clonal deletion results in apoptosis of most autoreactive B and T lymphocytes. Complete clonal deletion can lead to ... T lymphocytes can instead undergo clonal arrest, clonal anergy, and clonal editing. If autoreactive cells escape clonal ... Clonal deletion is the removal through apoptosis of B cells and T cells that have expressed receptors for self before ...
Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1.. Mazor T1, Chesnelong C2,3, ... Deletion or amplification of IDH1 was followed by clonal expansion and recurrence at a higher grade. Successful cultures ... Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1 ... Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1 ...
VßGene Family Usage in Spontaneous Lymphomas of AKR Mice: Evidence for Defective Clonal Deletion. Cees de Heer,1,2,3,4 Bernard ... The presence of V ß6+ lymphoma cells indicates that the lymphomagenesis is accompanied by a defective clonal deletion of cells ...
Here we identify mtDNA deletions as a driving force behind the premature aging phenotype of mitochondrial mutator mice, and ... DNA Deletions and Clonal Mutations Drive Premature Aging in Mitochondrial Mutator Mice Nat Genet. 2008 Apr;40(4):392-4. doi: ... Here we identify mtDNA deletions as a driving force behind the premature aging phenotype of mitochondrial mutator mice, and ... for a homology-directed DNA repair mechanism in mitochondria that is directly linked to the formation of mtDNA deletions. In ...
What is clonal deletion theory? Meaning of clonal deletion theory medical term. What does clonal deletion theory mean? ... Looking for online definition of clonal deletion theory in the Medical Dictionary? clonal deletion theory explanation free. ... clonal deletion theory. Also found in: Dictionary, Thesaurus, Legal, Encyclopedia. clo·nal de·le·tion the·o·ry. the elimination ... Clonal deletion theory , definition of clonal deletion theory by Medical dictionary https://medical-dictionary. ...
However, Bcl-xL was unable to block clonal deletion of thymocytes reactive with self-superantigens or H-Y antigen. These ... displays restricted distribution during T cell development and inhibits multiple forms of apoptosis but not clonal deletion in ... displays restricted distribution during T cell development and inhibits multiple forms of apoptosis but not clonal deletion in ...
Unusual clonal evolution involving 5q in a case of myelodysplastic syndrome with deletion 5q 31 treated with lenalidomide ... Unusual clonal evolution involving 5q in a case of myelodysplastic syndrome with deletion 5q 31 treated with lenalidomide ... Unusual clonal evolution involving 5q in a case of myelodysplastic syndrome with deletion 5q 31 treated with lenalidomide ... 2006) Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 355:1456-65. ...
Evidence for clonal deletion and anergy. E K Gao E K Gao ... Evidence for clonal deletion and anergy.. J Exp Med 1 April ... it is suggested that T cell contact with thymic epithelial cells induced clonal deletion of most of the host-reactive T cells ... deletion of V beta 11+ cells. Since marked tolerance was evident at the level of mature thymocytes, tolerance induction in the ... To account for the residual host reactivity of LN CD4+ cells and the incomplete deletion of V beta 11+ cells, ...
Antonyms for clonal deletion theory. 39 synonyms for theory: hypothesis, philosophy, system of ideas, plan, system, science, ... scheme, proposal, principles, ideology, thesis, belief, feeling.... What are synonyms for clonal deletion theory? ... Synonyms for clonal deletion theory in Free Thesaurus. ... Clonal deletion theory synonyms, clonal deletion theory ... clonal deletion theory provided by ,a style=color:#000 href=https://www.freethesaurus.com/clonal+deletion+theory, ...
... in which the predominant mechanism is clonal deletion of donor-specific T cells by donor hemopoietic cells in the recipient ... a low marrow dose generates tolerance with little evidence of clonal deletion. Only this low dose tolerance can be transferred ... We show here, for multiple minor Ag differences, that while a large inoculum of donor marrow produces significant deletion of ... Bone marrow transplantation induces either clonal deletion or infectious tolerance depending on the dose. ...
ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.atitle=Clonal%20deletion%20of%20potentially%20autoreactive%20T ... 20in%20mice&rft.date=1991&rft.au=Schneider,%20Reto&rft.genre=unknown&rft.btitle=Clonal%20deletion%20of%20potentially% ...
Clonal deletion of immature CD4+8+ thymocytes in suspension culture by extrathymic antigen-presenting cells *Wojciech Swat ... Rights & permissionsfor article Clonal deletion of immature CD4,sup,+,/sup,8,sup,+,/sup, thymocytes in suspension culture by ... T-cell-specific deletion of T-cell receptor transgenes allows functional rearrangement of endogenous α- and β-genes *Horst ... Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes *Pawel Kisielow ...
Clonal Deletion Theory of Immunity. Plant-based diets may be protective against multiple sclerosis because IGF-1 can prevent ... Clonal Selection Theory of Immunity. We may have a billion different types of antibody-releasing cells in our immune system, ...
Impaired peripheral clonal deletion in gp130F759/F759 mice. SEB (100 μg/mouse) was intraperitoneally injected into 6-wk-old ... Clonal Deletion In Vivo by Staphylococcal Enterotoxin B.. Staphylococcal enterotoxin B (SEB) (100 μg) (Toxin Technology) was ... Impairment of Thymic Negative Selection and Clonal Deletion in the Peripheral T Cells of gp130F759/F759 Mice In Vivo.. Both ... Then, we examined the effects of the Y759 mutation on the peripheral clonal deletion of activated T cells. For this study we ...
Clonal Deletion.png 1,440 × 816; 155 KB. *. Cluster of Differentiation mod.png 2,000 × 2,688; 245 KB. ...
Clonal Deletion.png 1.440×816; 155 kB. *. Cluster of Differentiation mod.png 2.000×2.688; 245 kB. ...
Myelodysplastic syndrome with isolated 5q deletion (5q- syndrome). A clonal stem cell disorder characterized by defective ... Myelodysplastic syndrome with isolated 5q deletion (5q- syndrome). A clonal stem cell disorder characterized by defective ... reported a distinct hematologic disorder associated with acquired deletion of the long arm of chromosome 5 [del(5q)]. This ... reported a distinct hematologic disorder associated with acquired deletion of the long arm of chromosome 5 [del(5q)]. This ...
Clonal Deletion of Self-Reactive T Cells. Positive Selection Model of the Origin of MHC-Restricted T Cells. Molecular ... Clonal Abortion versus Clonal Anergy. Clonal Abortion and Clonal Anergy Come of Age in the Molecular Era. The Genesis of High- ... The Deletion-Anergy Decision. Consequences of Deletion versus Anergy. References. 3 Tolerant Autoreactive B Lymphocytes in the ... Deletion or Anergy?. Does the Follicular Mantle Zone Serve as a Reform School for Wayward B Cells?. References. Part III ...
Effect of lenalidomide treatment on clonal architecture of myelodysplastic syndromes without 5q deletion ... MDS patients ... Myelodysplastic syndromes with 5q deletion: pathophysiology and role of lenalidomide ... and decreased miR-145 and miR-146a ... on response to lenalidomide and the drug effects on clonal evolution remain unknown. We ... ...
Effect of lenalidomide treatment on clonal architecture of myelodysplastic syndromes without 5q deletion ... MDS patients ...
Intrathymic and extrathymic clonal deletion of T cells. Curr. Opin. Immunol. 7: 196 (1995).PubMedCrossRefGoogle Scholar ... Requirement of a second signal from antigen presenting cells in the clonal deletion of immature T cells. Internat. Immunol. 6: ... Cellular and peptide requirements for in vitro clonal deletion of immature thymocytes. Proc. Natl. Acad. Sci. USA 89: 9000 ( ... T cell tolerance by clonal elimination in the thymus. Cell 49: 273 (1987).PubMedCrossRefGoogle Scholar ...
Failing either will result in clonal deletion or anergy. 1/100 emerge immunocompetent ...
Several mechanisms are involved in induction and maintenance of tolerance, including clonal deletion, clonal anergy, receptor ... Clonal deletion. The fate of B lymphocytes is governed by the specificity of their receptors. Encounter of a self‐reactive B ... Nemazee DA and Bürki K (1989) Clonal deletion of B lymphocytes in a transgenic mouse bearing anti‐MHC class I antibody genes. ... T lymphocytes specific for self‐peptides bound to major histocompatibility complex peptides are eliminated by clonal deletion, ...
clonal selection of b-cells. - make antibodies > mess up but do not kill. - produce memory cells to remember invaders ... clonal deletion lymphocytes recognize bodys own cells and molecules that are weeded out by apoptosis ...
clonal deletion, clonal anergy, functional deletion, generation of suppressor or regulatory T cells, blocking of presentation ...
  • T lymphocytes specific for self‐peptides bound to major histocompatibility complex peptides are eliminated by clonal deletion, a process known as negative selection. (els.net)
  • We have investigated the consequences of exposure to this prototypic B cell superantigen, and found that treatment of neonates or adults induces a T cell-independent deletion of a large supraclonal set of susceptible B cells that includes clan III/V H S107 family-expressing lymphocytes. (rupress.org)
  • However, these discoveries, and the host of allograft experiments and observations of twin chimerism they inspired, were seminal for the theories of immune tolerance formulated by Sir Frank McFarlane Burnet and Frank Fenner, who were the first to propose the deletion of self-reactive lymphocytes to establish tolerance, now termed clonal deletion. (wikipedia.org)
  • As IL-2 is an important inducer of lymphocyte proliferation, the absence of highly sensitive IL-2 receptors may also significantly hinder activation and clonal expansion of CD8+ and CD4+ lymphocytes and NK cells. (wikipedia.org)
  • Clonal Selection Algorithm: A class of algorithms inspired by the clonal selection theory of acquired immunity that explains how B and T lymphocytes improve their response to antigens over time called affinity maturation. (wikipedia.org)
  • Waldenström's macroglobulinemia is characterized by an uncontrolled clonal proliferation of terminally differentiated B lymphocytes. (wikipedia.org)
  • In CLL, the lymphocytes are genetically clonal, of the B cell lineage (expressing marker molecules clusters of differentiation 19 and 20), and characteristically express the marker molecules CD5 and CD23. (wikipedia.org)
  • Therefore, incomplete clonal deletion allows for a balance between the host's ability to recognize foreign antigens and self antigens. (wikipedia.org)
  • Recurrent KBTBD4 small in-frame insertions and absence of DROSHA deletion or DICER1 mutation differentiate pineal parenchymal tumor of intermediate differentiation (PPTID) from pineoblastoma. (ucsf.edu)
  • Further, clonal pattern of MCV insertions into MCC cell genomes indicates that the virus was present in the Merkel cell before it underwent cancerous transformation. (wikipedia.org)
  • Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter of a gene and affect its expression, or may occur in the gene's coding sequence and alter the function or stability of its protein product. (wikipedia.org)
  • Surveyor nuclease assay is an enzyme mismatch cleavage assay used to detect single base mismatches or small insertions or deletions (indels). (wikipedia.org)
  • The enzyme recognizes all base substitutions and insertions/deletions, and cleaves the 3′ side of mismatched sites in both DNA strands with high specificity This assay has been used to identify and analyze mutations in a variety of organisms and cell types, as well as to confirm genome modifications following genome editing (using CRISPR/TALENs/zinc fingers). (wikipedia.org)
  • These methods are simple to run using standard laboratory techniques and equipment, and can detect polymorphisms, single base pair mismatches, and insertions and deletions at low frequencies. (wikipedia.org)
  • Genomic instability may play an essential role in leukemogenesis by promoting the accumulation of genetic lesions responsible for clonal evolution. (mdpi.com)
  • The results of this study challenge previous reports indicating that alloreactive T cell elimination and thymic clonal deletion are primary mediators of PTCy efficacy and provide strong evidence to support FoxP3+CD4+ Tregs as important effectors of PTCy benefits. (jci.org)
  • Recent evidence suggests that increases in aging-associated mtDNA mutations are not caused by damage accumulation, but rather are due to clonal expansion of mtDNA replication errors that occur during development. (jci.org)
  • Yet there is evidence that more than 80% of the somatic mutations found in mutator phenotype human colorectal tumors occur before the onset of terminal clonal expansion. (wikipedia.org)
  • High-affinity self-reactive clones can die via clonal deletion, and the threshold between positive and negative selection is hypothesized to be steep. (nih.gov)
  • Some Tregs may have very highly self-reactive TCRs and are rescued from deletion via cytokine signaling or by virtue of having a second TCR (dotted line). (nih.gov)
  • The accumulation of heteroplasmic mitochondrial DNA (mtDNA) deletions and single nucleotide variants (SNVs) is a well-accepted facet of the biology of aging, yet comprehensive mutation spectra have not been described. (nih.gov)
  • A) Frequency of the common deletion per mtDNA (mtDNA −1 ), (B) Major-arc deletions, (C) CRMs, (D) CRDs. (nih.gov)
  • Clonal hypereosinophilia, also termed Primary hypereosinophelia or clonal eosinophilia, is a grouping of hematological disorder characterized by the development and growth of a pre-malignant or malignant population of eosinophils, a type of white blood cell, in the bone marrow, blood, and/or other tissues. (wikipedia.org)
  • But how the processes of thymocyte deletion versus Treg differentiation bifurcate and their relative importance for tolerance have not been studied in spontaneous organ-specific autoimmune disease. (nih.gov)
  • The memory B cell has already undergone clonal expansion and differentiation and affinity maturation, so it is able to divide multiple times faster and produce antibodies with much higher affinity (especially IgG). (wikipedia.org)
  • This process - called "clonal expansion" - allows the body to quickly mobilise an army of clones, as and when required. (wikipedia.org)
  • Negative selection via clonal deletion can also occur in the cortex, but occurs frequently in the medulla. (nih.gov)
  • This mouse is considered to be a superior repopulation model because spontaneous reversion does not occur with the full deletion of exon 5. (pnas.org)
  • Segmental aneuploidy can occur due to deletions, amplifications or translocations, which arise from breaks in DNA, while loss and gain of whole chromosomes is often due to errors during mitosis. (wikipedia.org)
  • DNA mismatches occur where one base is improperly paired with another base, or where there is a short addition or deletion in one strand of DNA that is not matched in the other strand. (wikipedia.org)
  • Clonal and subclonal mutations of NOTCH1 and TP53 , clonal mutations of SF3B1 , and ATM mutations in CLL have an impact on clinical outcome. (bloodjournal.org)
  • We identified a high proportion of subclonal mutations, isolated or associated with clonal aberrations. (bloodjournal.org)
  • However, many of the clonal hypereosinophilias are distinguished from these other hematological malignancies by the genetic mutations which underlie their development and, more importantly, by their susceptibility to specific treatment regiments. (wikipedia.org)
  • Based on their association with eosinophils, unique genetic mutations, and known or potential sensitivity to tyrosine kinase inhibitors or other specific drug therapies, they are now in the process of being classified together under the term clonal hypereosinophilia or clonal eosinophilia. (wikipedia.org)
  • Mutations in this gene were first identified in myeloid neoplasms with deletion or uniparental disomy at 4q24. (wikipedia.org)
  • In some instances, however, the repair is imperfect, resulting in deletion or insertion of base-pairs, producing frame-shift and preventing the production of the harmful protein. (wikipedia.org)
  • To monitor the editing activity, a PCR of the target area amplifies both alleles and, if one contains an insertion, deletion, or mutation, it results in a heteroduplex single-strand bubble that cleavage assays can easily detect. (wikipedia.org)
  • Several such enzymes have been discovered (including CEL I, T4 endonuclease VII, Endonuclease V, T7 endonuclease I). One of the commonly used enzymes is Surveyor nuclease (CEL II), which cleaves the 3′ side of both DNA strands with high specificity at sites of base substitution or insertion/deletion. (wikipedia.org)
  • DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage. (wikipedia.org)
  • Soluble protein but not peptide administration diverts the immune response of a clonal CD4+ T cell population to the T helper 2 cell pathway. (nih.gov)
  • Deletion or amplification of mutant IDH1 during malignant progression. (nih.gov)
  • If such a cell acquires additional genetic alterations providing a clonal advantage, this may lead to malignant transformation and ultimately to cancer [ 1 ]. (mdpi.com)
  • Positive selection occurs in the thymic cortex, which suggests it is possible for a cell to undergo positive selection within the cortex and then negative selection in the medulla via clonal deletion. (wikipedia.org)
  • Clonal evolution in longitudinal samples occurs before and after treatment and may have an unfavorable impact on overall survival. (bloodjournal.org)
  • suitable for breeding of new species A serious disadvantage of somaclonal variation occurs in operations which require clonal uniformity, as in the horticulture and forestry industries where tissue culture is employed for rapid propagation of elite genotypes. (wikipedia.org)
  • Once a primary rearrangement has been obtained, a secondary rearrangement may also use either deletion or inversion, depending on the orientation of the Vκ involved. (els.net)
  • Our goal is to understand the full evolutionary history of human brain tumors, from the first mutation and epimutation through clonal selection and tumor recurrence. (ucsf.edu)