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Peter Medawar Immunologic Basis of Graft Rejection The Behavior and Fate of Skin Autografts and Skin Homografts in Rabbits (A report to the War Wounds Committee of the Medical Research Council) By P.B. Medawar,*From the Department of Zoology and Comparative Anatomy University of Oxford •Inducibility •Memory •Specificity First Set Rejection Rejection 7-8 Days Second Set Rejection (Memory) First Graft Rejection 3-4 Days Specificity “Third Party” Graft Terminology Autograft - One site to another on the same individual Isograft - between two genetically identical individuals Terminology (cont.) Allograft - between genetically distinct individuals of the same species Xenograft - between different species Beginning of Rejection Rejected Mouse Skin Graft Rejection is mediated by T cells Role of CD4 and CD8 Cells Laws of Transplantation Tx between individuals of the same inbred strain will succeed. Tx between inbred strains are rejected. Tx parent to F1 will succeed, but the reverse will fail. Parent to F2 B B A B A AB AB A AA AB F1 F2 A AB AB B BA BB Survival Probability = 0.75 For 2 Loci: (0.75) x (0.75) % Graft Survival (P to F2) = (0.75)n n= Number of histocompatibility loci The Human MHC Class II Class III Class I DP DQ DR C4 C2 Bf B C E A G F Mixed Leukocyte Reaction Spleen 2000 RADS 5 Days Add 3H-Thymidine 18-24 Hours Spleen Determine Incorporation Acute Rejection Primary Cellular Massive infiltration of macrophages and lymphocytes Decreased graft function Clinically appears at >10 days post-tx and can occur anytime thereafter. Acute Rejection – Grade 1a Acute Rejection - Grade 3a Chronic Rejection Slow steady decline of graft function and progressive occlusion of of vessels/passageways. Result of cellular and humoral mechanisms Chronic Rejection Hyperacute Rejection Clinical Transplantation Objectives of Immunosuppression Facilitate acceptance of the allograft Specific Low toxicity Basic Strategies of Immunosuppression High dose initial immunospression Facilitate graft acceptance Minimize early rejection Favor induction of tolerance Maintenance therapy for chronic acceptance Augmentation to reverse acute rejection. Major Immunosuppressants Cyclosporine A Tacrolimus (FK-506) Sirolimus (Rapamycin) Steroids Azathioprine Mycophenylate Mofetil Medical Issues and Immunosuppression Selected Side Effects of Cyclosporine Gingival Hyperplasia Infection Nephrotoxicity Hypertension Tremors, Nightmares, Insomnia Hirsutism Fibrous Breast Tissue Infections Prophylactic Antibiotics for procedures with potential to cause bacteremia. Metabolism of some drugs may be altered, especially for liver transplant patients (e.g. acetominophin, lidocain, procain ampicillin etc). Graft Rejection Highly dependent on T cell activation and proliferation. Signaling pathways and control points for entry into cell cycle are appropriate targets for immunsuppression. Broad Mechanisms of Immunosuppression Inhibition of T cell activation. Block antigen binding. Block accessory molecules. Inhibition of IL-2 production. Inhibition of T cell proliferation. T cell depletion. Inhibition of B cell proliferation. Major Immunosuppressants Cyclosporine A Tacrolimus (FK-506) Sirolimus (Rapamycin) Steroids Azathioprine Mycophenylate Mofetil Inhibitors of T cell Receptor Signaling Cyclosporine Tacrolimus T cell Receptor Signaling Pathway Zap-70 Fyn PIP2 PLC IP3 DAG Ca2+ CaM Calcineurin T cell Signaling: Calcineurin Cyclosporine CaM Calcineurin Calcineurin Cyclophilin P NF-ATP NF-AT P Transcription Cytokine Gene NF-ATN Nucleus Immunosuppressants Monoclonal/Polyclonal Antibodies Antithymocyte Globulin CD3 (OKT3) CD25 ( Inhibitors of Cytokine Transcription Corticosteroids Antiproliferative Agents Azathioprine Mycophenylate mofetil Inhibition of Clonal Expansion Corticosteroids Mechanism Binds intracytoplasmic receptors Steroid/receptor complex migrates to nucleus Binds to gene promoters and NFAT Therefore impairs gene transcription of regulatory cytokines. Summary Immunosuppressive properties related to effects on T cell activation and proliferation. Inhibition of T cell activation and proliferation are associated with the most successful immunosuppression.
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