Transplantation Immunology Subscribe
Date: 23. November 2017
Immunologic Basis of Graft Rejection
The degree of immune response to a graft varies with the type of graft. The following terms are used to denote different types of transplants: Autograft is self-tissue transferred from one body site to another in the same individual. Isograft is tissue transferred between genetically identical individuals. Allograft is tissue transferred between genetically different members of the same species. Xenograft is tissue transferred between different species (e.g., the graft of a baboon heart into a human).
Tissues that are antigenically similar are said to be histocompatible; such tissues do not induce an immunologic response that leads to tissue rejection. Tissues that display significant antigenic differences are histoincompatible and induce an immune response that leads to tissue rejection. The various antigens that determine histocompatibility are encoded by more than 40 different loci, but the loci responsible for the most vigorous allograft-rejection reactions are located within the major histocompatibility complex (MHC). Cell-Mediated Graft Rejection occurs in two stages that are Sensitization Stage and Effector Stage.
Clinical Manifestations of Graft Rejection
Graft-rejection reactions have various time courses depending upon the type of tissue or organ grafted and the immune response involved. Hyperacute rejection reactions occur within the first 24 hours after transplantation, acute rejection reactions usually begin in the first few weeks after transplantation; and chronic rejection reactions can occur from months to years after transplantation. Graft tissue is rejected because of pre-existing antibodies.
Accelerated Rejection happens because of antibodies and is Formed immediately after transplant. Acute Rejection is mediated by T-Cell Responses: Cell-mediated allograft rejection manifests as an acute rejection of the graft beginning about 10 days after transplantation. Histopathologic examination reveals a massive infiltration of macrophages and lymphocytes at the site of tissue destruction, suggestive of TH-cell activation and proliferation. Chronic Rejection occurs months or years Post-Transplant: Chronic rejection reactions develop months or years after acute rejection reactions have subsided. The mechanisms of chronic rejection include both humoral and cell-mediated responses by the recipient.
Immunosuppressive measures are aimed at slowing the proliferation of activated lymphocytes. However, because any rapidly dividing nonimmune cells (e.g., epithelial cells of the gut or bone-marrow hematopoietic stem cells) are also affected, serious or even life-threatening complications can occur. Patients on long-term immunosuppressive therapy are at increased risk of cancer, hypertension, and metabolic bone disease.
Azathioprine (Imuran), a potent mitotic inhibitor, is often given just before and after transplantation to diminish T-cell proliferation in response to the alloantigens of the graft. Azathioprine acts on cells in the S phase of the cell cycle to block synthesis of inosinic acid, which is a precursor of the purines adenylic and guanylic acid. Both B-cell and T-cell proliferation is diminished in the presence of azathioprine. Two other mitotic inhibitors that are sometimes used in conjunction with other immunosuppressive agents are cyclophosphamide and methotrexate. Cyclophosphamide is an alkylating agent that inserts into the DNA helix and becomes cross-linked, leading to disruption of the DNA chain. It is especially effective against rapidly dividing cells and therefore is sometimes given at the time of grafting to block T-cell proliferation. Methotrexate acts as a folic-acid antagonist to block purine biosynthesis. The fact that the mitotic inhibitors act on all rapidly dividing cells and not specifically on those involved in immune response against the allograft can lead to deleterious side reactions by thwarting division of other functional cells in the body.
Immune Tolerance to Allografts
There are instances in which an allograft may be accepted without the use of immunosuppressive measures. Obviously, in the case of tissues that lack alloantigens, such as cartilage or heart valves, there is no immunologic barrier to transplantation. However, there are also instances in which the strong predicted response to an allograft does not occur.
In immunologically privileged sites, an allograft can be placed without engendering a rejection reaction. These sites include the anterior chamber of the eye, the cornea, the uterus, the testes, and the brain. The privileged location of the cornea has allowed corneal transplants to be highly successful. The brain is an immunologically privileged site because the blood-brain barrier prevents the entry or exit of many molecules, including antibodies. The successful transplantation of allogeneic pancreatic islet cells into the thymus in a rat model of diabetes suggests that the thymus may also be an immunologically privileged site.
For a number of illnesses, a transplant is the only means of therapy. certain combinations of organs, such as heart and lung or kidney and pancreas, are being transplanted simultaneously with increasing frequency
The most commonly transplanted organ is the kidney, many common diseases, such as diabetes and various types of nephritis, result in kidney failure that can be alleviated by transplantation. Since the first kidney transplant was performed in the 1950s, approximately 400,000 kidneys have been transplanted worldwide. The next most frequently transplanted solid organ is the liver (52,000), followed by the heart (42,000) and, more distantly, by the lung (6,000) and pancreas (2,000). Bone-marrow transplants number around 80,000. Although the clinical results of transplantation of various cells, tissues, and organs in humans have improved considerably in the past few years, major obstacles to the use of this treatment exist.
Bone-Marrow Transplants are used for Leukemia, Anemia, and Immunodeficiency, Since the early 1980s, bone-marrow transplantation has been increasingly adopted as a therapy for a number of malignant and nonmalignant hematologic diseases, including leukemia, lymphoma, aplastic anemia, thalassemia major, and immunodeficiency diseases, especially severe combined immunodeficiency, or SCID.
Heart Transplantation is a challenging operation: Perhaps the most dramatic form of transplantation is that of the heart; once the damaged heart has been removed, the patient must be kept alive by wholly artificial means until the transplanted heart is in place and beating. Heart-lung machines are available to circulate and aerate the patient’s blood after the heart is removed.
Liver Transplants Treat Congenital Defects and damage from Viral or Chemical Agents: The liver is a large organ that performs a number of functions related to clearance and detoxification of chemical and biological substances. Liver malfunction can be caused by damage to the organ from viral diseases such as hepatitis or by exposure to harmful chemicals, as in chronic alcoholism. Damage to the liver may correct itself and the damaged tissue can regenerate after the causative injurious agent is cleared. If the liver tissue does not regenerate, damage may be fatal. The majority of liver transplants are used as a therapy for congenital abnormalities of the liver.