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Transplantation Immunology

Transplantation Immunology. Laura Stacy March 22, 2006. Objectives. Name the different types of grafts Distinguish among the first-set, second-set, and chronic rejection Differentiate between host vs. graft rejection Describe serologic tests used for transplantation

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Transplantation Immunology

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  1. Transplantation Immunology Laura Stacy March 22, 2006

  2. Objectives • Name the different types of grafts • Distinguish among the first-set, second-set, and chronic rejection • Differentiate between host vs. graft rejection • Describe serologic tests used for transplantation • Understand the molecular basis of immune response • Appreciate the different tissues and organs that can be transplanted

  3. Outline • Introduction • The Immunology of Allogeneic Transplantation • Recognition of Alloantigens • Activation of Alloreactive T Cells and Rejection • Effector Mechanisms of Allograft Rejection • Hyperacute Rejection • Acute Rejection • Chronic Rejection • Xenogeneic Transplantation • Blood Transfusion • Bone Marrow Transplantation • Graft vs. Host Disease • Immunologic Analysis

  4. Introduction • A major limitation to the success of transplantation is the immune response of the recipient to the donor tissue. (Abbas pg 369)

  5. Terms • Autologous graft • Syngeneic graft • Allogeneic graft • Xenogeneic graft • Alloantigens • Xenoantigens • Alloreactive • xenoreactive

  6. First- and Second-set Allograft Rejection Figure 16.1

  7. The Immunology of Allogeneic Transplantation • Alloantigens elicit both cell-mediated and humoral immune responses. (Abbas pg 371) • Recognition of transplanted cells that are self or foreign is determined by polymorphic genes that are inherited from both parents and are expressed co-dominantly. (Abbas pg 371)

  8. Recognition of Alloantigens • Direct Presentation • Recognition of an intact MHC molecule displayed by donor APC in the graft • Basically, self MHC molecule recognizes the structure of an intact allogeneic MHC molecule • Indirect Presentation • Donor MHC is processed and presented by recipient APC • Basically, donor MHC molecule is handled like any other foreign antigen

  9. Molecular Basis of Direct Recognition Figure 16-4

  10. Direct and Indirect Recognition Figure 16-3

  11. Activation of Alloreactive T cells and Rejection of Allografts • Donor APCs migrate to regional lymph nodes and are recognized by the recipient’s T cells (Abbas pg 375) • Alloreactive T cells in the recipient may be activated by both pathways, and they migrate into the graft and cause graft rejection (Abbas pg 375)

  12. CD4+ and CD8+ • CD4+ differentiate into cytokine producing effector cells • Damage graft by reactions similar to DTH • CD8+ cells activated by direct pathway kill nucleated cells in the graft • CD8+ cells activated by the indirect pathway are self MHC-restricted

  13. Effector Mechanisms of Allograft Rejection • Hyperacute Rejection • Acute Rejection • Chronic Rejection

  14. Hyperacute Rejection • Characterized by thrombotic occlusion of the graft • Begins within minutes or hours after anastamosis • Pre-existing antibodies in the host circulation bind to donor endothelial antigens • Activates Complement Cascade • Xenograft Response

  15. Hyperacute Rejection: the early days • Mediated by pre-existing IgM alloantibodies • Antibodies come from carbohydrate antigens expressed by bacteria in intestinal flora • ABO blood group antigens • Not really a problem anymore

  16. Hyperacute Rejection: Today • Mediated by IgG antibodies directed against protein alloantigens • Antibodies generally arise from • Past blood transfusion • Multiple pregnancies • Previous transplantation

  17. Hyperacute Rejection 1. Preformed Ab, 2. complement activation, 3. neutrophil margination, 4. inflammation, 5. Thrombosis formation

  18. Acute Rejection • Vascular and parenchymal injury mediated by T cells and antibodies that usually begin after the first week of transplantation if there is no immunosuppressant therapy • Incidence is high (30%) for the first 90 days

  19. Acute Rejection • T-cell, macrophage and Ab mediated, • myocyte and endothelial damage, • Inflammation

  20. Chronic Rejection • Occurs in most solid organ transplants • Heart • Kidney • Lung • Liver • Characterized by fibrosis and vascular abnormalities with loss of graft function over a prolonged period (Abbas 381)

  21. Chronic Rejection • Macrophage – T cell mediated • Concentric medial hyperplasia • Chronic DTH reaction

  22. Types of Rejection • Acute Rejection: CD4 controlled CD8 mediated (8-11 days) • Hyperacute Rejection: pre-existing antibodies to donor tissue (7 min) • Chronic Rejection: Mixed CD4 and antibody – ”DTH like” (3 m to 10 years) • Xenograft Rejection: pre-existing antibodies to donor tissue (7 min)

  23. Xenogeneic Transplantation • A major barrier to xenogeneic transplantation is the presence of natural antibodies that cause hyperacute rejection. (Abbas pg 386)

  24. Most Common Transplantation-Blood Transfusion- Transfuse Not transfused

  25. Question Why are antibodies normally formed in response to ABO blood groups? • Due to prior exposure to blood • Maternal exposure • Gut flora • Plant pollen

  26. Question Why are antibodies normally formed in response to ABO blood groups? • Prior exposure to blood • Maternal exposure • Gut flora • Plant pollen

  27. Bone Marrow Transplantation • Rescue procedure for hemopoietic reconstitution subsequent to cancer chemo- or radio- therapy

  28. Graft vs. Host Disease • Caused by the reaction of grafted mature T-cells in the marrow inoculum with alloantigens of the host • Acute GVHD • Characterized by epithelial cell death in the skin, GI tract, and liver • Chronic GVHD • Characterized by atrophy and fibrosis of one or more of these same target organs as well as the lungs

  29. Heart Transplantation • Heart transplantation is indicated for those in end-stage heart disease with a New York Heart Association of class III or IV, • ejection fractions of <20%, • maximal oxygen consumption of (VO2) <14 ml/kg/min, and • expected 1-year life expectancy of <50%.

  30. Heart Transplantation • Survival is 80% at five years but at five year 50% also have coronary vascular disease due to chronic rejection.

  31. Transplantation • Kidney25,000 patients are waiting for kidney transplantation • savings in three years compared to the cost of three years of renal dialysis. • LiverOne-year survival exceeds 75% and five-year is 70%.

  32. Pancreas Transplantation • Graft survival is 72% at one-year and this is further improved if a kidney is transplanted simultaneously. • The overall goal of pancreas transplantation is to prevent the typical diabetic secondary complications: neuropathy, retinopathy, and cardiovascular disease.

  33. Immunologic Analysis • HLA Tissue Typing • Cytoscreen • Cross Match

  34. Questions?

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