immunology allergic disorders
Overview of Transplantation
Posttransplantation Immunosuppression
Immunosuppressants control graft rejection and are primarily responsible for the success of transplantation (see table Immunosuppressants Used to Treat Transplant Rejection ). However, they suppress all immune responses and contribute to many posttransplantation complications, including development of cancer, acceleration of cardiovascular disease, and even death due to overwhelming infection. Immunosuppressants must usually be continued long after transplantation, but initially high doses can be reduced a few weeks after the procedure, and low doses can be continued indefinitely unless rejection occurs. Further reduction of immunosuppressant doses long after transplantation and protocols for inducing tolerance of donor organs are under study. A high dose of corticosteroids is usually given at the time of transplantation, then the dose is reduced gradually to a maintenance dose, which is given indefinitely. Several months after transplantation, corticosteroids can be given on alternate days; this regimen helps prevent growth restriction in children. If rejection occurs, high doses are reinstituted. Regimens that reduce the need for corticosteroids (steroid-sparing regimens) are used in some centers and are being further refined. Two examples include use ofmycophenolateand mTOR inhibitors in combination with calcineurin inhibitors orbelatacept. These drugs (cyclosporine,tacrolimus) block T-cell transcription processes required for production of cytokines, thereby selectively inhibiting T-cell proliferation and activation. Cyclosporineis the most commonly used drug in heart and lung transplantation. It can be given alone but is usually given with other drugs (eg,azathioprine,prednisone), so that lower, less toxic doses can be used. The initial dose is reduced to a maintenance dose soon after transplantation. The drug is metabolized by the cytochrome P-450 3A enzyme, and blood levels are affected by many other drugs. The most serious dose-dependent adverse effect ofcyclosporineis nephrotoxicity;cyclosporinecauses vasoconstriction of afferent (preglomerular) arterioles, leading to glomerular damage, refractory glomerular hypoperfusion, and, possibly chronic renal failure. Also, B-cell lymphomas and polyclonal B-cell lymphoproliferation occur more often in patients receiving high doses ofcyclosporineor combinations ofcyclosporineand other immunosuppressants directed at T cells, possibly because of an association with Epstein-Barr virus. Other adverse effects include diabetes, hepatotoxicity, tophaceous gout, refractory hypertension, neurotoxicity (including tremor), increased incidence of other tumors, and less serious effects (eg, gum hypertrophy, hirsutism, hypertrichosis). Serumcyclosporinelevels do not tightly correlate with effectiveness or toxicity. Tacrolimusis the most commonly used drug in kidney, liver, pancreas, and small-bowel transplantation.Tacrolimusmay be started at the time of transplantation or days after the procedure. Dosing should be guided by blood levels, which are influenced by the same drug interactions as forcyclosporine.Tacrolimusmay be useful whencyclosporineis ineffective or has intolerable adverse effects. Adverse effects oftacrolimusare similar to those ofcyclosporineexcepttacrolimusis more prone to induce diabetes; gum hypertrophy and hirsutism are less common. In patients takingtacrolimus, lymphoproliferative disorders seem to occur more often, even just weeks after transplantation, and may resolve partly or completely when the drug is stopped. If lymphoproliferative disorders occur,tacrolimusshould be stopped, andcyclosporineor another immunosuppressive drug should be substituted. These drugs (azathioprine,mycophenolate) inhibit the proliferation of cells, particularly leukocytes. Azathioprine,an antimetabolite, is usually started at the time of transplantation. Most patients tolerate it indefinitely. The most serious adverse effects are bone marrow depression, especially in patients with thiopurine S-methyltransferase (TPMT) deficiency and, rarely, hepatitis or hepatic veno-occlusive disease. Systemic hypersensitivity reactions occur in > 5% of patients.Azathioprineis often used with low doses of calcineurin inhibitors. Mycophenolate, a prodrug metabolized to mycophenolic acid, reversibly inhibits inosine monophosphate dehydrogenase, an enzyme in the guanine nucleotide pathway that is rate-limiting in lymphocyte proliferation.Mycophenolateis given withcyclosporine(ortacrolimus) and corticosteroids to patients with a kidney, heart, or liver transplant. The most common adverse effects are leukopenia, nausea, vomiting, and diarrhea. It has replacedazathioprinein most transplant applications. These drugs (sirolimus,everolimus) block a key regulatory kinase (mammalian target of rapamycin [mTOR]) in lymphocytes, resulting in arrest of the cell cycle and in inhibition of lymphocyte response to cytokine stimulation. Sirolimusis typically given withcyclosporineand corticosteroids and may be useful for patients with renal insufficiency. Adverse effects include hyperlipidemia, interstitial pneumonitis, leg edema, impaired wound healing, and bone marrow depression with leukopenia, thrombocytopenia, and anemia. Everolimusis used to prevent kidney and liver transplant rejection. Adverse effects are similar to those ofsirolimus. Examples are Antilymphocyte globulin (ALG) Antithymocyte globulin(ATG) Both are fractions of animal antisera directed against human cells: Lymphocytes: ALG Thymus cells: ATG ALG and ATG suppress cellular immunity while preserving humoral immunity. They are used with other immunosuppressants to allow those drugs to be used in lower, less toxic doses. Use of ALG or ATG to control acute episodes of rejection improves graft survival rates; use at the time of transplantation may decrease rejection incidence and allow calcineurin inhibitors to be started later, thereby reducing toxicity. Use of highly purified serum fractions has greatly reduced incidence of adverse effects (eg, anaphylaxis, serum sickness, antigen-antibody–induced glomerulonephritis). Monoclonal antibodies directed against T cells provide a higher concentration of anti-T-cell antibodies and fewer irrelevant serum proteins than do ALG and ATG. Anti–IL-2 receptor monoclonal antibodiesinhibit T-cell proliferation by blocking the effect of IL-2, secreted by activated T cells.Basiliximab, which is a humanized anti–IL-2 receptor antibody and the only IL-2 receptor antibody still available, is used to treat acute rejection of kidney, liver, and small-bowel transplants; it is also used as adjunct immunosuppressive therapy at the time of transplantation. The only adverse effect reported is anaphylaxis, but an increased risk of lymphoproliferative disorders cannot be excluded. Belatacept, another antibody that inhibits T-cell costimulatory pathways, can be used in kidney transplant recipients. However, incidence of progressive multifocal leukoencephalopathy, a deadly central nervous system viral disorder, appears to be increased, and incidence of other viral infections is also increased. Posttransplant lymphoproliferative disorder is another concern.Belataceptis used in kidney transplant recipients who are at increased risk of nephrotoxicity resulting from calcineurin inhibitor use. Irradiation of a graft, local recipient tissues, or both can be used to treat kidney transplant rejection when other treatment (eg, corticosteroids and ATG) has been ineffective. Total lymphatic irradiation appears to safely suppress cellular immunity, at first by stimulation of suppressor T cells and later possibly by clonal deletion of specific antigen-reactive cells. However, because immunosuppressants are now so effective, the need for irradiation is extremely rare. Protocols and agents to induce graft antigen-specific tolerance without suppressing other immune responses are being sought. Two strategies are promising: Blockade of T-cell costimulatory pathways using a cytotoxic T lymphocyte–associated antigen 4 (CTLA-4)-IgG1 fusion protein Induction of chimerism (coexistence of donor and recipient immune cells, which may allow graft tissue to be recognized as self) using nonmyeloablative pretransplantation treatment (eg, withcyclophosphamide, thymic irradiation, ATG, andcyclosporine) to induce transient T-cell depletion, engraftment of donor hematopoietic stem cells, and subsequent tolerance of solid organ transplants from the same donor (under study) 