Transplantation Immunology PDF

Transplantation Immunology Dana M. Tofiq MBChB, FAAAAI Assistant Professor of Allergy & Immunology Learning Objectives By the end of this session, students should be able to: 1. Classify types of transplants (grafts) 2. Recognize histocompatibility and transplantation antigens 3. Compare the thre...

Transplantation Immunology Dana M. Tofiq MBChB, FAAAAI Assistant Professor of Allergy & Immunology Learning Objectives By the end of this session, students should be able to: 1. Classify types of transplants (grafts) 2. Recognize histocompatibility and transplantation antigens 3. Compare the three types of graft rejection 4. Define first-set and second-set graft rejections 5. Identify factors influencing allograft rejection 6. Illustrate the mechanism of graft rejection 7. Describe prevention of graft rejection and immunosuppressive therapy 8. Explain graft-versus-host disease Immune System Module Transplantation • Transfer of a graft or transplant (cells, tissues, or organs) from one site to another. • Individual from whom the transplant is taken is referred to as the donor. • Individual to whom it is transplanted, is called as the recipient. Immune System Module CLASSIFICATION OF TRANSPLANTS Based on Organ or tissue transplanted Explanation/ Examples Kidney, heart and skin grafts, etc. Based on the anatomical site of the graft Orthotopic grafts When the tissue or organ grafts are transplanted to their anatomically 'normal' sites in the recipient, then such grafts are known as orthotopic grafts. E.g., as in skin grafts. Heterotopic grafts are placed in anatomically 'abnormal' sites, as when thyroid tissue is transplanted in a subcutaneous pocket. Immune System Module CLASSIFICATION OF TRANSPLANTS Based on Explanation/ Examples Vital and static transplants Vital grafts Live grafts, such as the kidney or heart, are expected to survive and function physiologically in the recipient. Static grafts Nonliving structures, like bone or artery which merely provide a scaffolding on which new tissue is laid by the recipient Immune System Module CLASSIFICATION OF TRANSPLANTS Based on Explanation/ Examples Based on the genetic relationship between the donor and the recipient Autograft Self-tissue transferred from one part of the body site to another in the same individual. Example: • Transferring healthy skin to a burned area in burn patients. • Use of healthy blood vessels of the same person to replace blocked coronary arteries. Isograft or syngeneic graft Tissue transferred between genetically identical individuals (e.g. monozygotic twins) Immune System Module CLASSIFICATION OF TRANSPLANTS Based on Explanation/ Examples Based on the genetic relationship between the donor and the recipient Allograft Tissue transferred between genetically non-identical members of the same species (e.g. kidney or heart transplant). Xenograft Tissue transferred between different species. (e.g., the graft of a baboon heart into a man). Immune System Module Histocompatibility • Histocompatibility between the graft and recipient - decide whether the graft is going to be accepted or rejected. • Graft and recipient tissues histocompatible - graft is accepted. o Autografts and isografts are histocompatible. • Histoincompatible (i.e. antigenically dissimilar) grafts are generally rejected by the recipient. o Allografts and xenografts are usually histoincompatible. Immune System Module Transplantation Antigens • Antigens of allografts against which the recipient would mount an immune response. o MHC molecules o ABO and Rh blood group systems Immune System Module Transplantation Antigens • MHA (minor histocompatibility antigens): o Peptides derived from normal cellular proteins of donated organs. o Immune response against MHA molecules is weaker; hence they pose problems of rejection less frequently than MHC molecules. o One exception is when a graft is transferred from a male donor to a female recipient. Immune System Module Eichwald-Silmser Effect • The graft tissues of a male donor (XY) would have some male-specific minor histocompatibility (H-Y) antigens determined by the Y chromosome which will be absent in the female (XX) recipient. • It is observed that the rejection of grafts when transferred from a male donor to a female recipient, is more as compared to female to male transplantation. Immune System Module TYPES OF GRAFT REJECTION • Based of time taken for the rejection, types of immune response mounted against the graft and clinical & pathologic features: o Hyperacute o Acute o Chronic Immune System Module Hyperacute Rejection • Occurs within minutes to hours of transplantation. • Characterized by thrombosis of graft vessels and ischemic necrosis of the graft. • Mediated by circulating antibodies that are specific for antigens on the graft endothelial cells and that are present before transplantation. Immune System Module Hyperacute Rejection • Exposure to foreign HLA antigens can occur as a consequence of previous blood transfusions, pregnancy, or organ transplantation 🡪 develops antibodies against these antigens. • If an individual with these pre-existing antibodies to a foreign HLA antigen receives a graft🡪 graft rejected earlier and more vigorously. Immune System Module Preformed antibodies react with alloantigens on the vascular endothelium of the graft, activate complement (C) and trigger rapid intravascular thrombosis and necrosis of the vessel wall. Hyperacute Rejection • Not a common problem in clinical transplantation - because it can be avoided by matching the donor and the recipient. • Potential recipients are tested for antibodies against the prospective donor’s blood group antigens (by cross matching) and HLA antigens (by HLA typing). Immune System Module Acute Graft Rejection • Occurs within days or weeks after transplantation. • Due to an active immune response of the host stimulated by alloantigens in the graft. • Mediated by T cells (mainly cytotoxic T cells, occasionally helper T cells) and antibodies specific for alloantigens in the graft. • Cytotoxic T cells directly destroy the graft cells, or cytokines secreted by the helper T cells induce inflammation; which destroys the graft. Immune System Module Acute Graft Rejection • Antibodies contribute especially to the vascular component of acute rejection. • Antibody mediated injury to graft vessels by complement activation by the classical pathway. Immune System Module CD8 T cells react with graft alloantigens and destroy the endothelial and parenchymal cells or antibodies react with alloantigens of the graft's endothelium and causes endothelial cell damage via complement activation. Chronic Graft Rejection • Indolent form of graft damage that occurs over months or years, leading to progressive loss of graft function. • Manifested as fibrosis of the graft and by gradual narrowing of graft blood vessels, called graft arteriosclerosis. Immune System Module Chronic Graft Rejection • T cells that react against graft alloantigens secrete cytokines 🡪 stimulate the proliferation and activities of fibroblasts and vascular smooth muscle cells in the graft. T cells react with graft alloantigens may produce cytokines that induce inflammation and proliferation of intimal smooth muscle cells, leading to luminal occlusion and graft arteriosclerosis Immune System Module Comparison of various types of graft rejection Graft rejection Time taken for rejection Immune mechanisms involved Hyperacute Minutes to hours Preformed antibodies (Anti ABO and/or anti-HLA) Acute Weeks to months Cytotoxic T cell mediated Antibody mediated Chronic Months to years Chronic DTH mediated Antibody mediated Immune System Module FACTORS INFLUENCING ALLOGRAFT REJECTION • The rate of allograft rejection varies according to the: o Tissue involved o Genetic distance between the donor and recipient o Immunological memory Immune System Module Graft Acceptance and Graft Rejection • Pathological sequences that take place when a skin graft is placed: i) as an autograft to the same donor ii) as an allograft to a recipient for the first time (leads to first-set rejection) iii) as an allograft to the same recipient for the second time (leads to second-set rejection) Immune System Module Autograft Acceptance • When a skin graft is transplanted to the same individual at a different site: o Revascularization takes place by day 3-7 o Healing (within day 7-10) o Resolution and acceptance of the graft (by day 12-14). Immune System Module First-Set Rejection • Definition: Type of primary rejection when an allograft is placed for the first time from a donor to a recipient. • Immune System Module Second-Set Rejection • If, in a recipient that has rejected a graft by the first-set response, another graft from the same donor is transplanted, it will be rejected in an accelerated fashion. Immune System Module MECHANISM OF GRAFT REJECTION Graft rejection is caused principally by a T cell-mediated immune response to alloantigens expressed on the graft cells, primarily the MHC molecules. The T cell response to MHC antigens involves recognition of both the donor MHC molecule as well as the associated peptide ligand present in the cleft of the MHC molecule. ❖ The peptides present in the groove of allogeneic (i.e. donor) class I MHC molecules are derived from proteins synthesized within the allogeneic cell. ❖ The peptides present in the groove of allogeneic (i.e. donor) class II MHC molecules are generally proteins taken up and processed by the allogeneic APCs. Immune System Module MECHANISM OF GRAFT REJECTION The process of graft rejection can be divided into two stages: 1. Sensitization phase: which involves alloantigen (mainly graft MHC molecules) presentation to recipient’s T cells. 2. Effector stage: in which immune destruction of the graft takes place due to activation of recipient’s T cells. Immune System Module Sensitization Phase T cells in the recipient may recognize donor alloantigens in the graft in two different ways: direct pathway, and indirect pathway; depending on what cells in the graft are displaying these alloantigens to the recipient T cells. Immune System Module Direct Pathway of Alloantigen Presentation Many graft tissues contain antigen presenting cells (APCs, e.g. dendritic cells and macrophages) and when the tissues are transplanted, the APCs are also carried along with the graft to the recipients. ❖ The allogeneic MHC molecules on graft’s APCs are directly presented to the recipient’s helper T cells ❖ This pathway is responsible for most of the acute graft rejections mediated by cytotoxic T cells (described in effector phase). Immune System Module Indirect Pathway of Alloantigen Presentation This is similar to that for recognition of any foreign antigen by the host APCs. ❖ The graft cells are ingested by recipient APCs, donor alloantigens are processed and presented by the MHC molecules present on recipient APCs to recipient’s helper T cells. ❖ This pathway is responsible for most of the chronic rejection mediated by helper T cells via specialized form of chronic DTH reaction (described in effector phase). Immune System Module Effector Phase A variety of effector mechanisms participate in allograft rejection. The most common are cell-mediated reactions involving delayed-type hypersensitivity T cells and cytotoxic T cells. ❖ Delayed-type hypersensitivity: Activated helper T cells differentiate into TDTH cells. Cytokines secreted from TDTH (e.g. interferon-γ) activate macrophages which destroy the target graft cells by producing lytic enzymes. ❖ Cytotoxic T cells: CD8+ TC cells kill the graft cells by recognizing the allogeneic MHC-I molecules. Immune System Module Effector Phase ❖ Antibody-mediated mechanisms: Cytokines produced by helper T cells activate B cells to produce antibodies. Antibodies are also important in mounting immune response against the graft. They take a lead role in mediating hyperacute graft rejections; however, in acute and chronic rejections, they play a minor role. Antibody-mediated destruction of the graft occurs by the following mechanisms: ❑ Complement-mediated lysis ❑ Antibody-dependent cell-mediated cytotoxicity (ADCC) via NK cell or macrophage mediated destruction Immune System Module Mechanisms involved in graft rejection Immune System Module Prevention of Graft Rejection 1. Laboratory tests to determine histocompatibility Prior to transplantation, various laboratory tests should be carried out to assess the histocompatibility between the donor and recipient. ❖ ABO blood group compatibility testing by blood grouping and cross matching ❖ HLA typing Immune System Module Prevention of Graft Rejection 2. Immunosuppressive Therapy Hyperacute rejection manifests severely and within minutes, and so the treatment indicated is immediate removal of the tissue. Chronic rejection is generally considered irreversible and poorly amenable to treatment, only re-transplant generally indicated if feasible (though inhaled cyclosporine is being investigated to delay or prevent chronic rejection of lung transplants). Acute rejection is treated with therapeutic regimens consisting of one or combination of various immunosuppressive therapies. Immune System Module Immunosuppressive agents used to improve graft survival Immunosuppressive drugs Corticosteroids Prednisolone, hydrocortisone Calcineurin inhibitors Cyclosporine, Tacrolimus Mitotic inhibitors Azathioprine Cyclophosphamide Methotrexate Antiproliferatives Mycophenolic acid mTOR inhibitor (mammalian target of rapamycin) Sirolimus (rapamycin) Everolimus Immune System Module Immunosuppressive agents used to improve graft survival Monoclonal antibody based agents mAb to CD2 molecule present on T cell surface mAb to CD3 molecule present on T cell surface mAb to CD4 molecule present on T cell surface Monoclonal anti-IL-2Rα receptor antibodies OKT2 OKT3 OKT4 Basiliximab Daclizumab Monoclonal anti-CD20 antibodies Rituximab mAb to TNFα Anti-thymocyte globulin (ATG) Anti-lymphocyte globulin (ALG) Infliximab Immune System Module Graft-Versus-Host Disease (GVHD) • Graft mounts an immune response against the host (i.e. recipient) and rejects the host, in contrary to the usual situation of graft rejections, in which the recipient mounts an immune response against the graft antigens. • The GVHD occurs when the following three conditions are present: o Graft must contain immunocompetent T cells (e.g. stem cells or bone marrow or thymus transplants) o Recipient should possess transplantation antigens that are absent in the graft. o Recipient may be immunologically suppressed and therefore cannot mount immune response against the graft. Immune System Module Types of GVHD • Acute or fulminant GVHD o Occurs within first 100 days of post-transplantation. o Major challenge in case of bone marrow transplantation. • Chronic GVHD o Less severe form. o Occurs after 100 days of transplantation. Immune System Module GVHD • Clinical Manifestations o Acute GVHD: Damage to the liver (hepatomegaly), skin (rash), mucosa, and the intestine (diarrhea), mediated by graft’s immunocompetent T cell. Experimentally, GVHD can be produced in mice, called Runt disease. o Chronic GVHD: also attacks the above organs, but in addition, it causes damage to the connective tissues and exocrine glands. • Treatment: Glucocorticoids (administrated intravenously) are the standard treatment given for both acute and chronic GVHD. Immune System Module