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Immunologic Tolerance

Immunologic Tolerance. Contents. Part Ⅰ Introduction Part Ⅱ Development of Immunologic Tolerance Part Ⅲ Mechanism of Immunologic Tolerance Part Ⅳ Immunologic Tolerance and Clinic Medicine. Part Ⅰ Introduction.

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Immunologic Tolerance

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  1. Immunologic Tolerance

  2. Contents • Part Ⅰ Introduction • Part Ⅱ Development of Immunologic Tolerance • Part Ⅲ Mechanism of Immunologic Tolerance • Part Ⅳ Immunologic Tolerance and Clinic Medicine

  3. Part Ⅰ Introduction • 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

  4. General features of Immunologic 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.

  5. 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, its easier to induce and lasts longer in T cells than in B cell

  6. Difference of Immuologic tolerance & immunodeficiency, immunosuppression Immunodeficiency: any condition in which there is deficiency in the production of humoral and /or cell-mediated immunity---non-specificity to Ag Immunosuppression: The suppression of immune responses to antigens. This can be achieved by various means, including physical, chemical----non-specificity to Ag

  7. Part Ⅱ Development of Immunologic Tolerance

  8. 1. Induction of immunologic tolerance to antigen in fetal period and neonate period • Owen first observed immunologic tolerance to allogenic antigen in fetal period in 1945

  9. cattle of dizygotic twin

  10. Experiment of Medawar on immunologic tolerance

  11. 2. Induction of immunologic tolerance to antigen in adult Antigen and immunologic tolerance: • Concentration of antigens • Type of antigen: monomer, aggregates • Pathway of antigen entering body • Features of determinant: tolerogenic epitope • Variation of antigen

  12. High and low dose tolerance

  13. Tolerance in T and B cells

  14. Factors affecting tolerancerole of antigen

  15. Individual and immunologic tolerance: Heredity,Age, Gender, Health

  16. Factors affecting tolerancethe role of host

  17. Host age and antigen dose affect tolerance newborn adult

  18. Part Ⅲ Mechanism of Immunologic Tolerance

  19. 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

  20. 1. Central tolerance Clonal deletion (apoptotic cell death) During maturation of lymphocytes in the thymus for T cell or in the bone marrow for B maturation, immature lymphocytes that recognize ubiquitous self-antigen with high affinity are deleted bynegative selection

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

  22. Central Tolerance

  23. Negative selection of B cells inbone marrow

  24. 2. Peripheral tolerance ① clonal deletion and clonal ignorance: large tissue specific antigen delete specific T cells. self-reactive lymphocytes remain viable and functional but do not react to the self antigens in any detectable way. ② Clonal anergy and inactivation: functional inactivation without cell death: lack co-stimulatory signal

  25. Clonal anergy in T cells

  26. Clonal anergy in B cells

  27. ③ Action of Suppressor lymphocyte (Ts) ④ Action of cytokines: TGF- , IL-10 ⑤ Holdbackin signal tranduction ⑥Immunologically privileged sites anatomic barrier: clonal ignorance

  28. Pathways to Peripheral Tolerance Proliferation & differentiation Activated T cells NormalResponse B7 CD28 Antigen Recognitionwithout co-stimulation FunctionallyUnresponsive Anergy CTL4-B7 interaction CTLA4 B7 Fas Activation induced cell death Fas-FasL interaction Apoptosis FasL Inhibition of proliferation & effector action Cytokine-mediated suppression Cytokine regulation cytokines

  29. TCR MHC II B7 CD28 The Two Signal Hypothesis for T-cell Activation Signal 1 Mature Dendritic cell APC Activated TH cell TH cell Signal 2

  30. Resting B-cell APC TH0 cell CD28 Tolerance (anergy or apoptosis) from lack of signal 2 Hypothetical mechanism of tolerance in mature T cells Signal 1 Tolerant T cell

  31. Proliferation & differentiation B7 CD28 Anergy Antigen Recognitionwithout co-stimulation Summary: Lack of co-stimulation can lead to tolerance (anergy) Activated T cells NormalResponse

  32. CTLA4-B7 interaction FunctionallyUnresponsive (Anergic) T cell Regulation by CTLA-4 CTLA4 B7 Activated T cell

  33. Regulatory T cells Production of IL-10 or TGF-b FunctionallyUnresponsive T cell RegulatoryT cell

  34. Pathways to Peripheral Tolerance

  35. Inhibition by Antibody Feedback • Passively administered antibody can prevent an antibody response • Antibody produced during an immune responses leads to elimination of antigen (stimulus) • Less antigen available to stimulate specific cells • Immune complexes can bind to inhibitory receptors Application: RhoGam for Erythroblastosis Fetalis

  36. Major Immune Inhibitory Receptors • B cells • FcgRII • T cells • CTLA4 • NK cells • KIR (killer cell Ig-like receptors),

  37. Anti-Idiotypes and Immune Regulation • Definition • anti-idiotype response-antibody produced against immunoglobulin or TCR idiotypes that serve to down-regulate immune response • The epitope for an responsive anti-idiotype molecule (antibody, BCR, or TCR) is the internal image formed by the CDR region of the respective epitopes antigen receptor

  38. Idiotype/Anti-idiotype network

  39. Part Ⅳ Immunologic Tolerance and Clinic Medicine

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

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

  42. And now for a clinical case….

  43. Patient Presentation • 6 year old male, ER with unexplained bruising associated with minor trauma • Patient has minimal clotting activity • FVIII levels <1% of normal • Patient given i.v. FVIII concentrate i.v. and released but returns in two weeks with same problem • Repeated FVIII treatment • However, FVIII is ineffective.

  44. Issues • Coagulation factor inhibitors (anti-FVIII activity) • Basis? • Lack of tolerance. Why? • Prevalence/impact • 20-30% FVIII, less FIX • Treatment/problems • FVIII concentrate or rFVIII • Inhibitors develop that neutralize FVIII • Therapy? • Porcine FVIII with less cross-reactivity • Tolerance (high dose) • Gene therapy

  45. What are Inhibitors? • IgG; commonly subclass 4, mixed 1 & 4 • Occur in • Congenital factor deficiency = alloimmune • Previously unaffected = autoimmune • Associated with pregnancy, autoimmunity, malignancy, multi-transfusion, advanced age etc.

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