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Concept of Immune Regulation

Concept of Immune Regulation. Immune responses are tightly regulated complex interaction of cells & mediators, and by mechanisms to prevent anti-self reactivity Failure of regulatory control can occur…

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Concept of Immune Regulation

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  1. Concept of Immune Regulation • Immune responses are tightly regulated complex interaction of cells & mediators, and by mechanisms to prevent anti-self reactivity • Failure of regulatory control can occur… • Enhancement of immune responses or infection can generate autoimmune reactions (loss of self–tolerance) • Decrease of immune responses may lead to an immunodeficiency state • Shift in immune responses can lead to allergy

  2. Immunological Tolerance • History - Ehrlich, Owen, Burnet, • Billingham, Brent and Medawar

  3. Burnet’s Clonal Selection Model:Central Tolerance DEVELOPMENT MATURITY ClonalDeletion Anti-self Lymphocyte Self Ag Activation Differentiation Anti-non-self Lymphocyte Foreign Ag + second signal

  4. x Medawar’s experiment demonstrating neonatal tolerance induction (Nobel Prize)

  5. Immunological Tolerance • Definition and Properties • Specific unresponsive state induced by exposure to antigenic epitopes • Tolerance to self is initially induced during embryonic life, and is maintained by antigen • Tolerance occurs in both T and B cells • Multiple mechanisms of tolerance exist

  6. Central Tolerance

  7. Mechanisms of Immunological Tolerance - Overview • Central Tolerance through Clonal Deletion • Clones of cells that have receptors for self-antigens are deleted during development • Peripheral Tolerance • Clonal Anergy-failure of APC to deliver a second signal during antigen presentation (example: B7-CD28 interaction) • Suppression of responses may occur by production of regulatory T cells that inhibit immune response to self-antigen (example: TGF-, IL10 and Th1 vs. Th2 cytokines) • Ignorance to some self antigens may also exist

  8. Tolerance: Establishment and Failure Generation of immune repertoires Bone Marrow Thymus  Central Tolerance  Self-reactive lymphocytes Deleted by negative selection   Leakage of self-reactive lymphocytes controlled Peripheral Tolerance Wrong environment (viral infection?) Wrong genes or mutations Tolerance fails Autoimmune Diseases Global Therapies Selective

  9. Tolerance Exists in Both T and B Cells However, the Kinetics and Waning of Tolerance Induction Differs in T and B Lymphocytes

  10. 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

  11. 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

  12. 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

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

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

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

  16. Pathways to Peripheral Tolerance

  17. 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

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

  19. 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

  20. Idiotype/Anti-idiotype network

  21. Cytokines and Immune Regulation • Definition • Soluble mediators • Made by a variety of cells • Multifunctional proteins and peptides • Involved in initiating immune response • Involved in turning off immune response • Some serve as direct effector molecules (e.g., TNFa)

  22. Cytokine Regulation via TH1 – TH2 Balance High affinity Between TCR and APC High [Antigen] Th2 IFN-g IL-12 IL-4 IL-10 & TGF-b IL-18 Low affinity Between TCR and APC Low [Antigen] Th1

  23. Th1 versus Th2 Balance Disease Th1 Th2 Experimental Cure Progression Leishmaniasis Experimental autoimmune Progression Preventionencephalomyelitis Tuberculosis Cure/Prevention Progression Atopy Prevention? Progression Type 1 Diabetes (NOD) Progression Prevention

  24. CNS–Immune System Interactions CNS Hypothalamus Pituitary Adrenal gland Cytokines Antibodies Sympathetic nervous system Cytokines Activated Immune cells NE Immune System NE b2AR APC B cell CTL Th1 Th2

  25. Immunosuppression (adapted from Roitt) Anti-TCR, -CD3, CD4/8, CD45RB, LFA-1, ICAM-1 Anti-IL2 IL2R G0 G1 S G1/0 G2/M G0 Steroid CTLA-4-Fc-g fusion peptide UV Cyclosporin FK506 Steroid Rapamycin Azathoprine Methotrexate etc X-rays Cyclophosph.-amide

  26. And now for a clinical case….

  27. 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.

  28. 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

  29. 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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