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Chapter16 Immunological Tolerance

Chapter16 Immunological Tolerance. Contents. Part Ⅰ Introduction PartⅡ Mechanisms of Self Tolerance Part Ⅲ Factors affecting Induced Tolerance PartⅣ Clinical Significance of Immunological Tolerance. PartⅠ Introduction.

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Chapter16 Immunological Tolerance

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  1. Chapter16 Immunological Tolerance

  2. Contents PartⅠ Introduction PartⅡ Mechanisms of Self Tolerance PartⅢ Factors affecting Induced Tolerance PartⅣ Clinical Significance of Immunological Tolerance

  3. PartⅠ Introduction • Owen first observed immunological tolerance to allogenic antigen in fetal period in 1945

  4. cattle of dizygotic twin

  5. Experiment of Medawar on immunological tolerance

  6. Definition: A type of specific unresponsiveness to an antigen induced by the exposure of specific lymphocytes to that antigen, but response to other antigens. • Tolerogens: antigens that induce tolerance • Types: self-tolerance induced tolerance

  7. 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.

  8. Immunologic features of tolerance • It is an antigen-induced, active process • Like immunologic memory, it is antigen specific • Like immunologic memory, it can exist in B cells, T cells or both • Like immunologic memory, it's easier to induce and last longer in T cells than in B cells

  9. Tolerance in T and B cells

  10. Difference of Immuologic tolerance & immunodeficiency, immunosuppression Immunodeficiency:Deficiency in the production of humoral and /or cell-mediated immunity---non-specificity to Ag Immunosuppression: Suppression of immune responses to antigens. This can be achieved by various means, including physical, chemical----non-specificity to Ag

  11. Part II Mechanism of Self Tolerance

  12. 1. Central tolerance: Central tolerance occurs in the central lymphoid organs as a consequence of immature self-reactive 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

  13. 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 bynegative selection

  14. Clonal deletion:negative selection of T cells in the thymus

  15. Negative selection of B cells inbone marrow

  16. 2. Peripheral tolerance 1.Peripheral tolerance of T cells ① Clonal anergy functional inactivation without cell death: lack of co-stimulatory signal

  17. ②clonal ignorance: self-reactive lymphocytes remain viable and functional but do not react to the self antigens in any detectable way.

  18. ③ Immunologically privileged sites ④ Regulatory T cells CD4+CD25+ Treg: TGF- , IL-10 ⑤AICD(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.

  19. 2) Peripheral tolerance of B cells • ①Clonal deletion • ②Lack of Th cells • ③Clonal anergy • ④Receptor editing

  20. Part III Factors affecting tolerance induction • Role of antigen • Role of the host

  21. 1.role of antigens (1)Types of antigen • Large, aggregated, complex molecules, properly processed-immune response • soluble, aggregate-free, simple small molecules, not processed-tolerance (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 (4) features of determinant

  22. Immune response Low-zone tolerance high-zone tolerance T、B cell T cells 抗体滴度 TD-Ag TI-Ag TD-Ag Concentration of antigen

  23. 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

  24. Host age and antigen dose affect tolerance newborn adult

  25. PartⅣ Clinical Significance of immunological tolerance

  26. 1. To induce immunological tolerance • Prevent the rejection of organ allografts and xenografts • Treat autoimmune diseases • Treat allergic diseases

  27. 2. To terminate immunological tolerance • To treat tumor: enhance first signal or second signal • To treat infection diseases

  28. Summary • Definition of immunological tolerance • Features of immunological tolerance • Induction of immunological tolerance • Mechanism of immunological tolerance • Clinical application of immunological tolerance

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