Organ Graft Rejection PDF

Organ Graft Rejection Dr Felix N. Toka Professor, Veterinary Immunology & Virology Department of Biomedical Sciences Objectives of the topic Explain different types of tissue or organ grafts Summarize the genetics of graft rejection Describe the allograft rejection Pre...

Organ Graft Rejection Dr Felix N. Toka Professor, Veterinary Immunology & Virology Department of Biomedical Sciences Objectives of the topic Explain different types of tissue or organ grafts Summarize the genetics of graft rejection Describe the allograft rejection Present the mechanism of allograft tissue destruction Present the strategies of preventing graft rejection Explain the graft-versus-host disease  What role of the immune system does rejection of a foreign organ graft reflect? The rejection of a foreign organ graft simply reflects the role of the immune system in identifying and destroying non-self (“abnormal” cells)  Types of organ grafts AUTOGRAFT: ISOGRAFT: When tissue is moved Graft transplanted to a different part of an between two genetically animal’s own body - identical individuals – does not trigger an does not cause an immune response immune response e.g., skin to cover a burn, segment of vein to bypass blocked cardiac arteries ALLOGRAFTS: Tissue transplanted between genetically different members of the same species, e.g., Eg The most frequent type of graft Difference in MHC and blood group antigens induces a strong immune response - rejection of graft Xenografts: Organ grafts transplanted between animals of different species e.g., the transplant of a baboon heart into a human infant Will cause the strongest immune reaction to reject the graft  Renal allografting is now routine in dogs and cats Bone marrow allografts appear useful in some forms of tumor therapy Most current organ grafts are obtained from healthy donor animals Is it ethical? Genetics of graft rejection Genetics of graft rejection cont’d Grafts between genetically identical individuals are never rejected Grafts between genetically non-identical individuals are always rejected Offspring of genetically different individuals will not reject grafts from either parent. (This rule is violated by bone marrow transplantation, when NK cells in an [A x B] F1 recipient do reject bone marrow cells from either parent) A graft from the offspring of two genetically different individuals will be rejected by either parent Allograft Rejection Allografted organs are a major source of foreign molecules, which include: Blood group antigens MHC molecules, (both class I and class II) Mechanisms of rejection are the same irrespective of grafted tissue Antibodies and T cells participate in the rejection  Acute rejection process the grafted tissue gradually becomes infiltrated with cytotoxic T cells, Section of a canine kidney during acute rejection densely infiltrated with lymphocytes. progressive damage to the endothelial cells lining small blood vessels  T cell-mediated damage induces chemokines that attract more T cells into the graft cellular destruction, stoppage of blood flow, hemorrhage, and death of the grafted organ follow thrombosis of the vessels a repeated graft from the same donor will involve antibodies and the complement, so the graft will be rapidly rejected Clinical Renal Allograft Rejection* Rejection can occur at anytime Hyperacute rejection - occurs within 48 hours after grafting Accelerated rejection - occurs up to 7 days after grafting Acute rejection - occurs after 7 days Chronic rejection - develops several months after grafting *Based on human classification – no consensus if this can be used in veterinary medicine  Once kidney blood vessels are connected and blood supply resumes, host and donor cells mix In unsensitized individuals, rejection can take place after at least 10 days In sensitized individuals, hyperacute rejection occurs immediately Manifestation of acute rejection Kidney is use as an example for recipient shows a rapidly rising blood creatinine Transplat any organ enlarged, painful kidney signs of depression, anorexia, vomiting, proteinuria, hematuria, ultrasonography shows an enlarged, hypoechoic kidney Signs of chronic rejection should be save pavanters bt theyrise gradually creatinine and urea levels rise gradually Proteinuria macroscopic hematuria a small, hyperechoic kidney Pathogenesis of Allograft Rejection The allograft rejection process is directed against the dominant antigens on the cells of the graft The MHC molecules trigger T cell responses Blood group antigens trigger antibody formation Two stages of the rejection process 1. host’s lymphocytes encounter the antigens of the graft and trigger a response – direct pathway 2. cytotoxic T cells and antibodies from the host enter the graft and destroy graft cells – indirect pathway  Graft rejection pathways Direct pathway Indirect pathway Mechanism of graft destruction Hyperacute rejection: thrombotic occlusion of the graft vasculature starts within minutes to hours after host-graft blood vessels are anastomosed is mediated by preexisting antibodies in the host circulation that bind to donor endothelial antigens Hyperacute rejection of a kidney allograft with endothelial damage, platelet and thrombin thrombi, and early neutrophil infiltration in a glomerulus  Mechanism of graft destruction cont’d Acute rejection: injury to the graft parenchyma and blood vessels mediated by alloreactive T cells and antibodies inflammation caused by cytokines produced by helper T cells and CTL-mediated killing of graft parenchymal cells and endothelial cells preexisting host antibodies bind to donor endothelial antigens and cause damage Acute cellular rejection of a kidney with inflammatory cells in the connective tissue around the tubules and between epithelial cells of the tubules Mechanism of graft destruction cont’d Chronic rejection: Sameprocess but at a low speed arterial occlusion due to proliferation of intimal smooth muscle cells graft eventually fails due to ischemic damage Chronic rejection in a kidney allograft with graft arteriosclerosis. The vascular lumen is replaced by an accumulation of smooth muscle cells and connective tissue in the vessel intima Prevention of Allograft Rejection The main aim: Minimal immunosuppression to prevent rejection, and not make the recipient more susceptible than necessary to infection General strategies: Inhibitors of T Cell Signaling Pathways – e.g., cyclosporine and FK506 (tacrolimus) prevent excessive cytokine production (e.g., IL-2) Antimetabolites - metabolic toxins that kill proliferating T cells are used e.g., azathioprine, mycophenolate mofetil Prevention of Allograft Rejection cont’d Function-Blocking or Depleting Anti-Lymphocyte Antibodies e.g., anti- thymocyte globulin, anti-CD3 Costimulatory Blockade - Drugs that block T cell costimulatory pathways e.g., CTLA4-Ig, which binds to B7 molecules, Targeting Alloantibodies and Alloreactive B Cells – e.g., plasmapheresis and anti-CD20 respectively Anti-inflammatory Drugs – e.g., corticosteroids Prevention of Allograft Rejection cont’d In dogs, azathioprine, leflunomide, prednisolone, and cyclosporine are used Without treatment, allografts in dogs are rejected within 6-14 days simultaneous bone marrow allograft from the donor animal or treatment with rabbit antidog thymocyte serum enhances graft survival Prevention of Allograft Rejection cont’d In cats, prednisolone and cyclosporine are used Can be supplemented with ketoconazole (ketoconazole suppresses cyclosporine metabolism in the liver and prolongs its half-life) Graft-Versus-Host Disease (GVHD) GVHD is caused by the reaction of grafted mature T cells in the bone marrow inoculum with alloantigens of the host occurs when the host is immunocompromised and cannot reject grafted cells may occur in individuals immunosuppressed by total-body irradiation or cyclophosphamide treatment  Acute GVHD: causes epithelial cell death in the skin, liver (mainly the biliary epithelium), and gastrointestinal tract. manifested clinically by rash, jaundice, diarrhea, and gastrointestinal hemorrhage Chronic GVHD: is characterized by fibrosis and atrophy of one or more of the same organs, without evidence of acute cell death Very severe cutaneous erythematous lesions on the face of a dog suffering from graft-versus-host disease as a result of a bone marrow allograft.