TRANSPLANTATION & tissue rejection

1. TRANSPLANTATION&tissue rejection

2. Organ transplantation: Is the moving of an organ from one body to another for the purpose of replacing the recipient's damaged or failing organ with a working one from the donor site. Organ donors can be living or deceased Organs that can be transplanted: the heart, kidneys, liver, lungs, pancreas, eyes and intestine. Tissuesthat can be transplanted: bones, tendons, cornea, heart valves, veins, and skin

3. Types of transplants 1.Autograft • Transplant of tissue to the same person. e.g. skin, vein, stem cells 2.Allograft: • Transplant of an organ or tissue between two genetically non-identical members of the same species • Most human tissue and organ transplants are allografts 3.Isograft:(Syngeneic) • A subset of allografts from a donor to a genetically identical recipient (e.g. identical twin). • Isografts don't trigger an immune response. 4.Xenograft: • A transplant of organs or tissue from one species to another • e.g. porcine heart valve transplants

4. Immunologic Basis of Allograft Rejection Grafts rejection Is a kind of specific immune response to the organ which causes failure of the transplant • Specificity • Immune memory Transplantation antigens: • Major histocompatibility antigens (MHC molecules) • Minor histocompatibility antigens • Other alloantigens

5. Major histocompatibility antigens (MHC molecules) • Main antigens of grafts rejection • Cause fast and strong rejection • Difference of HLA types is the main cause of human grafts rejection • Minor histocompatibility antigens • Also cause grafts rejection, but slow and weak • Other alloantigens • ABO blood group antigens • Some tissue specific antigens: • Skin, kidney, heart, pancreas ,liver • VEC (vascular endothelial cell) antigens

6. Mechanism of allograft rejection • Cell-mediated Immunity • Humoral Immunity • Role of NK cells Cell-mediated Immunity • T cell-mediated cellular immune response against alloantigens on grafts • T cells of the recipient recognize the allogeneic MHC molecules i.e. uptake and presentation of allogeneic donor MHC molecules by recipient APCs • activated CD4+T cells  MΦ activation and recruitment • Activated CD8+T cells  Kill the graft cells

7. Humoral immunity • Important role in hyperacute rejection • Complements activation • ADCC • Opsonization Role of NK cells • mediators secreted by activated Th cells can promote NK activation

8. Classification of Allograft Rejection • Host versus graft reaction (HVGR) Conventional organ transplantation • Graft versus host reaction (GVHR) Bone marrow transplantation

9. Host versus graft reaction (HVGR) • Hyperacute rejection • Acute rejection • Chronic rejection

10. Hyperacute rejection • Occurs within minutes to hours after host blood vessels are anastomosed to graft vessels • Pathology: • Thrombotic occlusion of the graft vasculature • Ischemia, denaturation, necrosis • Mechanisms: • Antibody against ABO blood type antigen • Antibody against VEC antigen • Antibody against HLA antigen • Complement activationEndothelial cell damage • Platelets activation  Thrombosis, vascular occlusion, ischemic damage

11. Acute rejection • Occurs within days to 2 weeks after transplantation, 80-90% of cases occur within 1 month • Pathology • Acute humoral rejection: Acute vasculitis manifested mainly by endothelial cell damage • Acute cellular rejection: Parenchymal cell necrosis along with infiltration of lymphocytes and MΦ • Mechanisms • Vasculitis: IgG antibodies against alloantigens on endothelial cell • Parenchymal cell damage • Delayed hypersensitivity mediated by CD4+Th1 • Killing of graft cells by CD8+Tc

12. Chronic rejection • Develops months or years after acute rejection reactions have subsided • Pathology • Fibrosis and vascular abnormalities with loss of graft function • Mechanisms • Not clear • Extension and results of cell necrosis in acute rejection • Chronic inflammation mediated by CD4+T cell/MΦ • Organ degeneration induced by non immune factors

13. Graft versus host reaction (GVHR) • Graft versus host reaction (GVHR) • Allogeneicbone marrow transplantation. • Rejection to host alloantigens. • Mediated by immune competent cells in bone marrow. • Graft versus host disease (GVHD) • A disease caused by GVHR, which can damage the host. • Acute GVHD • Chronic GVHD • Conditions • Enough immune competent cells in grafts. • Immunocompromised host. • Histocompatability differences between host and graft.

14. 1. Acute GVHD • Endothelial cell death in the skin, liver, and gastrointestinal tract • Rash, jaundice, diarrhea, gastrointestinal hemorrhage • Mediated by mature T cells in the grafts 2. Chronic GVHD • Fibrosis and atrophy of one or more of the organs • Eventually complete dysfunction of the affected organ Both acute and chronic GVHD are commonly treated with intense immunosuppresion

15. Prevention and Therapy of Allograft Rejection • Tissue Typing • ABO and Rh blood typing • HLA typing (HLA-A and HLA-BHLA-DR) • Screening of the recipient for anti-HLA antibodies (also called antibody screening) • Lymphocyte cross matching (also called compatibility testing) • Immunosuppressive Therapy • Corticosteroids: block the synthesis and secretion of cytokines • Azathioprine, Cyclophosphamide: block the proliferation of lymphocytes.