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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 • 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 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. 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 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 Part Ⅱ Development of Immunologic Tolerance 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 cattle of dizygotic twin Experiment of Medawar on immunologic tolerance 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 High and low dose tolerance Tolerance in T and B cells Factors affecting tolerance role of antigen Factors which affect response Favor immune response Favor tolerance Physical form of antigen Large, aggregated, complex molecules, properly processed soluble, aggregate-free, simple small molecules, not processed Route of injection Subcutaneous or intramuscular Oral or, sometimes, intravenous Dose of antigen Optimal dose Very large or very small dose Individual and immunologic tolerance: Heredity, Age, Gender, Health Factors affecting tolerance the role of host Factors that affect response Favor immune response Favor tolerance Age of responding animal Fully differentiated; memory T & B cells Newborn (mice), immunologically immature Differentiation state of cells Older, immunologically mature Relative undifferentiated B cell with only IgM, T cells in the thymic cortex Host age and antigen dose affect tolerance newborn adult Part Ⅲ Mechanism of Immunologic Tolerance 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 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 by negative selection Clonal deletion: negative selection of T cells in the thymus Central Tolerance Negative selection of B cells in bone marrow 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 costimulatory signal Clonal anergy in T cells Clonal anergy in B cells ③ Action of Suppressor lymphocyte (Ts) ④ Action of cytokines: TGF- , IL-10 ⑤ Holdback in signal tranduction ⑥ Immunologically privileged sites anatomic barrier: clonal ignorance Pathways to Peripheral Tolerance Proliferation & differentiation Normal Response Activated T cells CD28 B7 Antigen Recognition without co-stimulation Anergy CTL4-B7 interaction Functionally Unresponsive CTLA4 B7 Activation Fas induced cell death Fas-FasL interaction Apoptosis FasL Cytokine-mediated suppression Cytokine regulation cytokines Inhibition of proliferation & effector action The Two Signal Hypothesis for T-cell Activation Signal 1 MHC II Mature Dendritic cell APC B7 TCR Activated TH Tcell H cell CD28 Signal 2 Hypothetical mechanism of tolerance in mature T cells Signal 1 Resting B-cell APC Tolerant T H0 cell T cell CD28 Tolerance (anergy or apoptosis) from lack of signal 2 Summary: Lack of co-stimulation can lead to tolerance (anergy) Normal Response Proliferation & differentiation CD28 B7 Anergy Antigen Recognition without co-stimulation Regulation by CTLA-4 CTLA4 CTLA4-B7 interaction B7 Activated T cell Functionally Unresponsive (Anergic) T cell Regulatory T cells Production of IL-10 or TGF- Regulatory T cell Functionally Unresponsive T cell Pathways to Peripheral Tolerance 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 Major Immune Inhibitory Receptors • B cells – FcgRII • T cells – CTLA4 • NK cells – KIR (killer cell Ig-like receptors), 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 Idiotype/Anti-idiotype network Part Ⅳ Immunologic Tolerance and Clinic Medicine 1. To induce immunologic tolerance • • • Prevent the rejection of organ allografts and xenografts Treat autoimmune diseases Treat allergic diseases 2. To terminate immunologic tolerance • To treat tumor: enhance first signal or second signal • To treat infection diseases And now for a clinical case…. 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. 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 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. Summary Definition of immunologic tolerance Features of immunologic tolerance Induction of immunologic tolerance Mechanism of immunologic tolerance Clinical application of immunologic tolerance