Immunosuppressive therapy in transplantation

Immunosuppressants suppress graft rejection and the primary response to transplantation itself. However, they suppress all types of immune response and play a role in the development of numerous post-transplant complications, including death from severe infections. Except when HLA-identical grafts are used, immunosuppressants are used long-term after transplantation, but initial high doses may be tapered within a few weeks after the procedure, and then low doses may be given indefinitely unless graft rejection is a concern.

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Glucocorticoids

High doses are usually given at the time of transplantation, then gradually reduced to a maintenance dose, which is given indefinitely. A few months after transplantation, glucocorticoids can be given every other day; this helps prevent growth failure in children. If there is a risk of rejection, the patient is given high doses again.

Calcineurin inhibitors

These drugs (cyclosporine, tacrolimus) block the transcription process in T-lymphocytes responsible for the production of cytokines, resulting in selective suppression of the proliferation and activation of T-lymphocytes.

Cyclosporine is most commonly used in heart and lung transplants. It can be given alone, but is usually used in combination with other drugs (azathioprine, prednisolone), allowing it to be given in lower, less toxic doses. The initial dose is reduced to a maintenance dose soon after transplantation. This drug is metabolized by the cytochrome P-450 3A enzyme, and its blood levels are affected by many other drugs. Nephrotoxicity is the most serious side effect; cyclosporine causes vasoconstriction of the afferent (preglomerular) arterioles, leading to glomerular damage, uncorrectable glomerular hypoperfusion, and de facto chronic renal failure. B-cell lymphomas and polyclonal B-cell lymphoproliferative disorders, possibly related to Epstein-Barr virus, have been reported in patients receiving high doses of cyclosporine or combinations of cyclosporine with other immunosuppressants that target T lymphocytes. Other adverse effects include hepatotoxicity, refractory hypertension, increased incidence of other neoplasms, and less serious side effects (gingival hypertrophy, hirsutism). Serum cyclosporine levels do not correlate with efficacy or toxicity.

Tacrolimus is most commonly used in kidney, liver, pancreas, and intestinal transplants. Tacrolimus treatment may be started at the time of transplantation or within a few days afterward. Dosage should be adjusted based on blood levels, which may be affected by interactions with other drugs, such as those that affect cyclosporine levels. Tacrolimus may be useful if cyclosporine is ineffective or if intolerable side effects develop. Side effects of tacrolimus are similar to those of cyclosporine, except that tacrolimus predisposes more to diabetes; gingival hypertrophy and hirsutism are less common. Lymphoproliferative disorders appear to be more common in patients receiving tacrolimus, even several weeks after transplantation. If these occur and a calcineurin inhibitor is required, tacrolimus is stopped and cyclosporine is started.

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Purine metabolism inhibitors

This group of drugs includes azathioprine and mycophenolate mofetil. Treatment with azathioprine, an antimetabolite, is usually started at the time of transplantation. Most patients tolerate it well for as long as desired. The most serious side effects are bone marrow suppression and, less commonly, hepatitis. Azathioprine is often used in combination with low doses of cyclosporine.

Mycophenolate mofetil (MMF), a precursor metabolized to mycophenolic acid, reversibly inhibits inosine monophosphate dehydrogenase, an enzyme in the guanine nucleotide pathway that is the rate-limiting substance for lymphocyte proliferation. MMF is used in combination with cyclosporine and glucocorticoids in kidney, heart, and liver transplants. The most common side effects are leukopenia, nausea, vomiting, and diarrhea.

Rapamycins

These drugs (sirolimus, everolimus) block a key regulatory kinase in lymphocytes, resulting in cell cycle arrest and suppression of the lymphocyte response to cytokine stimulation.

Sirolimus is usually given to patients with cyclosporine and glucocorticoids and is most useful in patients with renal failure. Side effects include hyperlipidemia, impaired wound healing, suppression of red bone marrow activity with leukopenia, thrombocytopenia and anemia.

Everolimus is commonly prescribed to prevent heart transplant rejection; its side effects are similar to those of sirolimus.

Immunosuppressive immunoglobulins

This group of drugs includes antilymphocyte globulin (ALG) and antithymocyte globulin (ATG), which are fractions of animal antiserum obtained by immunizing them with human lymphocytes or thymocytes, respectively. ALG and ATG suppress the cellular immune response, although the humoral immune response remains. These drugs are used with other immunosuppressants, which allows these drugs to be used in lower, less toxic doses. The use of ALG and ATG helps control acute rejection, increasing the rate of graft survival; their use during transplantation can reduce the rate of rejection and allow cyclosporine to be administered later, which reduces the toxic effect on the body. The use of highly purified serum fractions has made it possible to significantly reduce the incidence of side effects (such as anaphylaxis, serum sickness, glomerulonephritis induced by the antigen-antibody complex).

Monoclonal antibodies (mAbs, mAds)

Anti-T-lymphocyte mAbs produce higher concentrations of anti-T-lymphocyte antibodies and lower amounts of other serum proteins than ALG and ATG. Currently, the only murine mAb used in clinical practice is OKTZ. OKTZ inhibits T-cell receptor (TCR) binding to antigen, resulting in immunosuppression. OKTZ is used primarily to treat acute rejection episodes; it can also be used during transplantation to reduce the incidence or suppress the onset of rejection. However, the benefits of prophylactic administration must be weighed against potential side effects, which include severe cytomegalovirus infection and the formation of neutralizing antibodies; these effects are eliminated when OKTZ is used during actual rejection episodes. During the first use, OKTZ binds to the TKP-CD3 complex, activating the cell and triggering the release of cytokines that lead to fever, chills, myalgia, arthralgia, nausea, vomiting, diarrhea. Preliminary administration of glucocorticoids, antipyretics, antihistamines can alleviate the condition. The reaction to the first administration less often includes chest pain, dyspnea and wheezing, possibly due to activation of the complement system. Repeated use leads to an increase in the frequency of B-cell lymphoproliferative disorders induced by the Epstein-Barr virus. Meningitis and hemolytic uremic syndrome are less common.

Anti-IL-2 receptor mAbs inhibit T-cell proliferation by blocking the effect of IL-2, which is secreted by activated T lymphocytes. Basiliximab and dacrizumab, two humanized anti-T (HAT) antibodies, are increasingly being used to treat acute rejection of kidney, liver, and intestinal transplants; they are also used as an adjunct to immunosuppressive therapy during transplantation. Adverse effects include reports of anaphylaxis, and isolated trials suggest that daclizumab, when used with cyclosporine, MMF, and glucocorticoids, may increase mortality. In addition, studies with anti-IL-2 receptor antibodies are limited, and an increased risk of lymphoproliferative disorders cannot be excluded.

Irradiation

Irradiation of the graft, a localized portion of the recipient tissue, or both may be used to treat cases of kidney transplant rejection when other treatments (glucocorticoids, ATG) are ineffective. Total lymphatic irradiation is experimental but appears to safely suppress cellular immunity primarily by stimulating suppressor T cells and possibly later by clonal killing of specific antigen-reactive cells.

Therapy of the Future

Currently, methods and drugs are being developed that induce antigen-specific graft tolerance without suppressing other types of immune response. Two strategies show promise: blockade of the T-cell costimulatory pathway using cytotoxic T-lymphocyte-associated antigen 4 (CT1_A-4)-1g61 fusion protein; and induction of chimerism (coexistence of donor and recipient immune cells in which the transplanted tissue is recognized as self) using non-myeloablative pretransplant treatments (eg, cyclophosphamide, thymic irradiation, ATG, cyclosporine) to induce short-term T-cell depletion, engraftment of donor HSCs, and subsequent tolerance to solid organ grafts from the same donor.