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Transcript
Chapter 16 Immunological Tolerance Contents PartⅠ Introduction PartⅡ Mechanisms of Self Tolerance PartⅢ Factors affecting Induced Tolerance PartⅣ Clinical Significance of Immunological Tolerance PartⅠ Introduction • Owen first observed immunological tolerance to allogenic antigen in fetal period in 1945 cattle of dizygotic twin • Graft of Skin From A to B or From B to A ----No rejection A B Experiment of Medawar on immunological tolerance Immunological tolerance Definition: A type of specific unresponsiveness to an antigen induced by the exposure of specific lymphocytes to that antigen, but response to other antigens normally. • Tolerogens: antigens that induce tolerance • Types: self-tolerance induced tolerance General features of immunological tolerance • Tolerance is antigenic specific and results from the recognition of antigens by specific lymphocytes. • Normal individuals are tolerant of their own antigens(self antigen)----- Self-tolerance. • Foreign antigens may be administered in ways that preferentially inhibit immune response by inducing tolerance in specific lymphocytes---antigen induction. Immunologic features of tolerance It is an antigen-induced, active process Like immunologic memory, it is antigen specific It can exist in B cells, T cells or both • Tolerance in T cell is longer lasting than B cell. Tolerance in T and B cells Difference of Immuologic tolerance & immunodeficiency, immunosuppression Immunodeficiency:Deficiency in the production of humoral and /or cell-mediated immunity--non-specificity to Ag Immunosuppression: S uppression of immune responses to antigens. This can be achieved by various means, including physical, chemical---non-specificity to Ag Part II Mechanism of Self Tolerance 1. Central tolerance: Central tolerance occurs in the central lymphoid organs as a consequence of immature selfreactive lymphocytes recognizing ubiquitous self-antigen. 2. Peripheral tolerance: tolerance was induced in peripheral organs as a result of mature self-reactive lymphocytes encountering tissue-specific self antigens under particular conditions 1. Central tolerance Clonal deletion (apoptotic cell death) During maturation of T lymphocytes in the thymus or B lymphocytes in the bone marrow, immature lymphocytes that recognize ubiquitous self-antigen with high affinity are deleted by negative selection Clonal deletion: negative selection of T cells in the thymus Clonal Selection of T cells in the Thymus Negative selection of B cells in bone marrow Clonal deletion of B cells in the bone marrow Stem cell (in red bone marrow) B cells BCRs Cell with autoantigens Cell with autoantigens Apoptosis Blood vessel To spleen 2. Peripheral tolerance 1)Peripheral tolerance of T cells ① Clonal anergy functional inactivation without cell death: lack of costimulatory signal ②clonal ignorance: self-reactive lymphocytes remain viable and functional but do not react to the self antigens in any detectable way. Clonal anergy Clonal ignorance ③ Regulatory T cells CD4+CD25+Foxp3+ Treg: TGF- , IL-10 ④ AICD( activation-induced cell death) Repeated stimulation of lymphocytes by persistent antigens results in death of the activated cells by a process of apoptosis. --- FasL on activated T cell binds to Fas on activated T cell and then induces T cell apoptosis. ⑤ Immunologically privileged sites Anatomic Barrier Immunological Suppression: TGF- , IL-10 2) Peripheral tolerance of B cells Clonal deletion :AICD Lack of Th cell help : Th cell anergy Clonal anergy : express insensitive mIg lack costimulatory molecules Receptor editing : from self-reactive B cell clone to foreign antigen-reactive B cell lone Part III Factors affecting tolerance induction 1. Role of antigen 2. Role of the host 1.Role of antigens (1)Types of antigen • Large, aggregated, complex molecules, properly processedimmune response • soluble, aggregate-free, simple small molecules, not processedtolerance (2)Dosage of antigen • Optical dosage-immune response • Very high or very low-tolerance (3)Portal of entry • Subcutaneous or intramuscular-immune response • Oral or intravenous-tolerance Tolerance:Oral >Intravenous>Intraperitoneal>Intramuscular>subcutaneous (4) features of determinant Concentration of antibody Immune response Low-zone tolerance high-zone tolerance T cells T、B cell TD-Ag TD-Ag TI-Ag Concentration of antigen 2.Role of the host (1)Ages • Adult, immunologically mature---Immune response • Embryo and newborn , immunologically immature--immunological tolerance (2) Differentiation state of cells • Fully differentiated; memory T & B cells—Immune response • Relative undifferentiated B cell with only IgM, T cells in the thymic cortex---immunological tolerance (3) Species,Heredity, Gender, Health Host age and antigen dose affect tolerance newborn adult PartⅣ Clinical Significance of immunological tolerance 1. To induce immunological tolerance • • • Prevent the rejection of organ allografts and xenografts Treat autoimmune diseases Treat allergic diseases 2. To terminate immunological tolerance • To treat tumor: enhance first signal or second signal • To treat infection diseases Summary Definition of immunological tolerance Features of immunological tolerance Induction of immunological tolerance Mechanism of immunological tolerance Clinical application of immunological tolerance