Table of Contents
Important Definitions in Transplantation Medicine
Xenografts were the first to be tried in transplantation medicine. They are described as the transplantation of a solid organ from a different species into the human body. A common example are pig heart valves. This form of transplantation carried the highest risk of rejection until the introduction of immunosuppressive drugs.
Autografts are grafts from the same individual. Examples include skin grafts and bone marrow transplantation from a previously stored cord blood sample.
Isografts are transplants between two genetically identical individuals, monozygotic twins.
Allografts are the most common type of transplants nowadays. They include transplants between genetically non-identical individuals in the same species, human-to-human kidney transplant, for example. Allografts should be matched promptly to lower the risk of rejection, and immunosuppression is usually indicated.
Immunologic Matching Between Donor Organ and Recipient
The first identified antigen that plays a critical role in the rejection process of transplanted organs is the major histocompatibility complex, also known as the human leukocyte antigen (HLA). Transplanted tissues have these surface antigens, which, if matched improperly, allow the recipient’s immune system to identify the tissue as foreign and to attack. HLA can be classified into three main classes.
- Class I HLAs are present on the cell surface of all nucleated cells and are encoded by the HLA-A, HLA-B and HLA-C genes on chromosome 6.
- Class II HLAs are mainly present on immune cells such as activated B-cells, macrophages and activated T-cells. They can be also present on the endothelium and on epithelial cells. They are encoded by the HLA-D genes.
- HLA class III antigens determine the complement factors C2, C3 and B. Because the HLA-A to D genes are very close to each other, they are usually inherited as one block with minimal cross-over. 25% of siblings are therefore found to be genetically identical for the HLA classes.
The ABO system plays an important role in blood transfusion reactions, but ABO incompatibility has a minimal role in solid organ rejection. Tissues that are highly vascularized, such as the kidneys, can undergo hyperacute rejection in case of ABO incompatibility, hence ABO matching for these transplants might be necessary. Immunosuppressive therapy ameliorates this problem.
Donor-recipient HLA matching is extremely important to lower the risk of graft rejection. First, it is important to identify which HLA antigens are expressed on the cell surface of leukocytes from the donor and the recipient and to confirm their matching.
Second, one should mix cells from the donor with recipient immune cells and look for any immunologic response to surface antigens. More recently, HLA matching is done via DNA typing which allows for rapid identification of the different HLA antigens the donor’s organ might express.
To ensure ABO compatibility, it is important to do serologic cross-matching after HLA matching. The cause of hyperacute rejection, in case of ABO incompatibility, is preformed serum antibodies against ABO surface antigens, which are expressed on the surface of highly vascularized tissues such as the kidneys.
Serum from the recipient is mixed with cells from the donor’s organ, and the pathologist should look for any signs of hyperacute rejection. If there is ABO incompatibility, but the patient needs the transplant urgently, and there are no other alternatives, plasmapheresis can be used to wash out any preformed antibodies, and the transplantation can be performed after that.
Transplantation of partially HLA compatible bone marrow into a recipient might cause graft-versus-host-disease, which can be fatal. Recent advances in depleting T-cells in the donor’s bone marrow before transplantation lowered the risk of graft-versus-host-disease significantly.
Mechanisms of Transplant Rejection
A solid organ transplant might be rejected by alloimmune antibodies, leukocytes mediated or cytokines mediated mechanisms.
Preformed antibodies are responsible for hyperacute rejection of mismatched ABO organs or for patients undergoing a second transplant from the same donor. The preformed antibodies bind to HLA and ABO antigens in the endothelium, recruit complement factors and eventually lead to the formation of a thrombus. Multiple thrombi in the feeding vessels to the transplanted organ eventually result in necrosis and rejection.
In case of poorly matched HLA antigens, leukocytes identify the tissue as foreign, and a T-cell mediated immune response starts. T-cells get activated, release different proinflammatory cytokines and recruit CD4+ and CD8+ T-cells in addition to B-cells and other inflammatory cells.
The different immunologically active cells infiltrate the transplanted organ and eventually destroy it. This process can happen in months to years, in case of a partially HLA matched tissue; in weeks, in case of poorly matched tissues, and in days, if the patient had pre-existing anti-donor T-cells due to a previous transplant from the same donor.
Transplantation Immunosuppression Therapy
Radiation therapy and the use of anti-metabolite agents usually target hematopoietic stem cells. They are recommended before a bone marrow transplantation. Before the transplanted bone marrow starts functioning, the patient is at an increased risk of opportunistic infections due to cytopenia.
Additionally, patients are at an increased risk of sterility and alopecia because the formation of sperm and hair is dependent on highly metabolic active cells, which can be affected by anti-metabolite agents or radiation.
Calcineurin inhibitors such as cyclosporine and tacrolimus are used to inhibit T-cell mediated rejection. Both drugs act by preventing the synthesis of different cytokines known to be responsible for activating and recruiting other leukocytes in the immune response initiated against the grafted organ.
Sirolimus blocks the action of different cytokine receptors, such as interleukin-2, interleukin-4 and interleukin-10 receptors. It can be used in combination with cyclosporine for a synergistic effect.
Immunosuppression Therapy for Specific Transplants
In kidney transplantation, cyclosporine is the immunosuppressive of choice to prevent acute and chronic rejection. In case of acute rejection, high dosage methylprednisolone can be used to salvage the transplanted kidney. Patients who develop hyperacute rejection should have the transplanted kidney removed.
Liver transplant recipients should be started on tacrolimus, followed by mycophenolate combined with steroids. This regimen improved survival in patients with liver transplants.
Patients undergoing a heart transplantation should be prescribed prednisone after the operation, which should be discontinued once the endomyocardial biopsy is completely normalized. Tacrolimus should be given after that time-point. It can be combined with mycophenolate.
In all the above cases, anti-Interleukin-2-receptor antibodies should be used for induction therapy before the transplantation.
Patients undergoing bone marrow transplantation are at the highest risk of developing graft-versus-host-disease. It is important to prevent this process from happening in the first place because management of severe graft-versus-host-disease is usually futile.
Prevention is achieved by removing all T-cells from the donor’s bone marrow and blood before the transplantation. Treatment of mild to moderate graft-versus-host-disease includes steroids, cyclosporine and mycophenolate.