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Peter Medawar

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.

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Peter Medawar

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  1. Peter Medawar

  2. 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

  3. First Set Rejection Rejection 7-8 Days

  4. Second Set Rejection (Memory) First Graft Rejection 3-4 Days

  5. Specificity Rejection 3-4 Days Rejection 7-8 Days “Third Party” Graft

  6. Terminology Autograft - One site to another on the same individual Isograft - between two genetically identical individuals

  7. Terminology (cont.) Allograft - between genetically distinct individuals of the same species Xenograft - between different species

  8. Beginning of Rejection

  9. Rejected Mouse Skin Graft

  10. Rejection is mediated by T cells

  11. Role of CD4 and CD8 Cells

  12. 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.

  13. Parent to F2 B B A B A A AA AB AB AB F2 F1 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

  14. The Human MHC Class I Class III Class II DP DQ DR C4 C2 Bf B C E A G F

  15. Mixed Leukocyte Reaction Spleen 5 Days 2000 RADS Add 3H-Thymidine 18-24 Hours Spleen Determine Incorporation

  16. 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.

  17. Acute Rejection – Grade 1a

  18. Acute Rejection - Grade 3a

  19. Chronic Rejection • Slow steady decline of graft function and progressive occlusion of of vessels/passageways. • Result of cellular and humoral mechanisms

  20. Chronic Rejection

  21. Hyperacute Rejection

  22. Clinical Transplantation

  23. Objectives of Immunosuppression • Facilitate acceptance of the allograft • Specific • Low toxicity

  24. 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.

  25. Major Immunosuppressants • Cyclosporine A • Tacrolimus (FK-506) • Sirolimus (Rapamycin) • Steroids • Azathioprine • Mycophenylate Mofetil

  26. Medical Issues and Immunosuppression • Selected Side Effects of Cyclosporine • Gingival Hyperplasia • Infection • Nephrotoxicity • Hypertension • Tremors, Nightmares, Insomnia • Hirsutism • Fibrous Breast Tissue

  27. 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).

  28. 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.

  29. 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.

  30. Major Immunosuppressants • Cyclosporine A • Tacrolimus (FK-506) • Sirolimus (Rapamycin) • Steroids • Azathioprine • Mycophenylate Mofetil

  31. Inhibitors of T cell Receptor Signaling • Cyclosporine • Tacrolimus

  32. T cell Receptor Signaling Pathway

  33. T cell Signaling: Calcineurin Calcineurin

  34. Immunosuppressants • Monoclonal/Polyclonal Antibodies • Antithymocyte Globulin • CD3 (OKT3) • CD25 ( • Inhibitors of Cytokine Transcription • Corticosteroids

  35. Antiproliferative Agents • Azathioprine • Mycophenylate mofetil

  36. Inhibition of Clonal Expansion

  37. Corticosteroids • Mechanism • Binds intracytoplasmic receptors • Steroid/receptor complex migrates to nucleus • Binds to gene promoters and NFAT • Therefore impairs gene transcription of regulatory cytokines.

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