immunological tolerance

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 Immunological Tolerance • History - Ehrlich, Owen, Burnet, –Billingham, Brent and Medawar Burnet’s Clonal Selection Model: Central Tolerance DEVELOPMENT Clonal Deletion Anti-self Lymphocyte Self Ag MATURITY Activation Differentiation Anti-non-self Lymphocyte Foreign Ag + second signal x Medawar’s experiment demonstrating neonatal tolerance induction (Nobel Prize) 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 Central Tolerance 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 Tolerance: Establishment and Failure Generation of immune repertoires Bone Marrow  Thymus Central Tolerance  Self-reactive lymphocytes Deleted by negative selection  Wrong environment (viral infection?) Peripheral Tolerance Tolerance fails  Leakage of self-reactive Wrong genes or mutations lymphocytes controlled Autoimmune Diseases Global Therapies Selective Tolerance Exists in Both T and B Cells However, the Kinetics and Waning of Tolerance Induction Differs in T and B Lymphocytes Pathways to Peripheral Tolerance Normal Response CD28 B7 Antigen Recognition without co-stimulation Proliferation & differentiation Activated T cells Anergy CTL4-B7 interaction CTLA4 B7 Functionally Unresponsive Activation Fas induced cell death FasL Fas-FasL interaction Apoptosis Cytokine-mediated suppression Cytokine regulation cytokines Inhibition of proliferation & effector action The Two Signal Hypothesis for T-cell Activation Signal 1 MHC II TCR Mature Dendritic cell APC Activated TH Tcell H cell B7 CD28 Signal 2 Hypothetical mechanism of tolerance in mature T cells Signal 1 Resting B-cell APC CD28 Tolerant TH0 cell T cell 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 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) Cytokine Regulation via TH1 – TH2 Balance Th2 High affinity Between TCR and APC IFN-g IL-4 IL-10 & TGF- IL-12 IL-18 Low affinity Between TCR and APC High [Antigen] Th1 Low [Antigen] Th1 versus Th2 Balance Disease Experimental Leishmaniasis Th1 Cure Th2 Progression Experimental autoimmune encephalomyelitis Tuberculosis Atopy Type 1 Diabetes (NOD) Progression Prevention Cure/Prevention Prevention? Progression Progression Progression Prevention CNS–Immune System Interactions Cytokines Antibodies CNS Hypothalamus Activated Immune cells Cytokines Pituitary Sympathetic nervous system NE Adrenal gland Immune System NE  2AR APC B cell Th1 Th2 CTL Immunosuppression (adapted from Roitt) Anti-TCR, -CD3, CD4/8, CD45RB, LFA-1, ICAM-1 Anti-IL2 IL2R G0 G0 G1 S G2/M G1/0 Steroid CTLA-4-Fc-g fusion peptide Cyclosporin FK506 Steroid Rapamycin Azathoprine X-rays Methotrexate etc UV Cyclophosph.amide 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? • Prevalence/impact • Lack of tolerance. Why? • 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.