Immunosuppressive therapy for transplant

Immunosuppressants suppress transplant rejection and a primary response to the transplant 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 for a long time after transplantation, but initial high doses can be reduced within a few weeks after the procedure, and then low doses can be administered arbitrarily long if there is no threat of rejection transplant.

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Glucocorticoids

High doses are usually prescribed during transplantation, then the dose is gradually reduced to a supporting dose, which is taken infinitely long. A few months after transplantation, you can go to the regimen of taking glucocorticoids every other day; Such a regimen helps to prevent growth disorders in children. If there is a threat of rejection, the patient is again assigned high doses.

Calcineurin Inhibitors

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

Cyclosporine is most commonly used for heart and lung transplantation. It can be prescribed on its own, but it is usually used together with other drugs (azathioprine, prednisolone), which allows it to be administered at lower, less toxic doses. The initial dose is reduced to a supporting dose shortly after transplantation. This drug is metabolized by the enzyme of the cytochrome P-450 ZA system and many other drugs affect its level in the blood. Nephrotoxicity is the most serious side effect; Cyclosporine causes vasoconstriction of bringing (precursor) arterioles, leading to damage to the glomerular apparatus, which is not amenable to the correction of glomerular hypoperfusion and actually chronic renal failure. In patients receiving high doses of cyclosporine or a combination of cyclosporine with other immunosuppressants acting on T lymphocytes, B-cell lymphomas and polyclonal B-cell lymphoproliferative disorders, possibly associated with the Epstein-Barr virus, are detected. Other undesirable effects include hepatotoxicity, refractory hypertension, increased incidence of other tumors, and less serious side effects (gingival hypertrophy, hirsutism). The level of serum cyclosporine does not correlate with its effectiveness or toxicity.

Tacrolimus is most often used in the transplantation of the kidneys, liver, pancreas, intestines. Treatment with tacrolimus can be started during transplantation or for several days after it. Dosage should be adjusted depending on the level of the drug in the blood, which may be affected by interaction with other drugs, the same ones that affect the blood content of cyclosporine. Tacrolimus can be useful if cyclosporine is ineffective or unbearable side effects develop. Side effects of tacrolimus are similar to those of cyclosporine, except that tacrolimus is more predisposed to the development of 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 this occurs and the administration of a calcineurin inhibitor is required, the administration of tacrolimus ceases and cyclosporin is administered.

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Purine metabolism inhibitors

To this group of drugs include azathioprine and mofetil mycophenolate. Treatment with azathioprine, antimetabolite usually begins during transplantation. Most patients tolerate it well for as long as you like. The most serious side effects are suppression of red bone marrow activity and less often hepatitis. Azathioprine is often used in combination with low doses of cyclosporine.

Mofetil Mycophenolate (MMF), a precursor metabolized to mycophenolic acid, reversibly suppresses inosine monophosphate dehydrogenase, the enzyme of the guanine nucleotide pathway, which is a substance that limits the rate of proliferation of lymphocytes. MMF is prescribed in combination with cyclosporine and glucocorticoids for kidney, heart and liver transplantation. The most common side effects are leukopenia, nausea, vomiting and diarrhea.

Rapamycins

These drugs (sirolimusus, everolimus) block the key regulatory kinase in lymphocytes, which results in stopping the cell cycle and suppressing the response of lymphocytes to cytokine stimulation.

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

Everolimus is usually prescribed to prevent rejection of a heart transplant; the side effects of this drug are the same as in sirolimusus.

Immunosuppressive immunoglobulins

This group of drugs includes antilymphocytic globulin (ALG, ALG-antilymphocyte globulin) and antitymocyte globulin (ATG, antigemocyte globulin) that are a fraction of the antiserum of animals obtained by immunization with human lymphocytes or thymocytes, respectively. ALG and ATH suppress the cellular immune response, although the humoral immune response persists. These drugs are used with other immunosuppressants, which allows using these drugs in lower, less toxic doses. Using ALG and ATG allows to control acute rejection, increasing the frequency of graft survival; use them during transplantation can reduce the incidence of rejection and allow later to appoint cyclosporine, which reduces the toxic effect on the body. The use of highly purified serum fractions significantly reduced the incidence of side effects (such as anaphylaxis, serum sickness, glomerulonephritis induced by the antigen-antibody complex).

Monoclonal antibodies (mAb, mAds)

MAT against T-lymphocytes provide a higher concentration of anti-T-lymphocyte antibodies and fewer other serum proteins compared to ALG and ATH. At present, only mouse MAT - OKTZ is used in clinical practice. OCT inhibits the binding of the T-cell receptor (TCR) to the antigen, resulting in immunosuppression. OKTZ is used mainly for arresting episodes of acute rejection; it can also be used during transplantation to reduce the frequency or suppress the onset of rejection. However, the benefits of prophylactic use should be comparable to possible side effects, which include severe cytomegalovirus infection and the formation of neutralizing antibodies; these effects are eliminated when using OKTZ in the period of real episodes of rejection. During first use, OKTZ binds to the TKP-CD3 complex, activating the cell and triggering the release of cytokines, which lead to fever, chills, myalgia, arthralgia, nausea, vomiting, diarrhea. The prescription of glucocorticoids, antipyretics, antihistamines can alleviate the condition. The response to the first administration is less likely to include chest pain, dyspnoea 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. Less common are meningitis and hemolyticcouremic syndrome.

MAT to the IL-2 receptor 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, HAT-humanized anti-T) antibodies are increasingly being used to treat acute rejection of kidney, liver, and intestinal graft; they are also used as an adjunct to immunosuppressive therapy during transplantation. Among the side effects there is a report of anaphylaxis, and carrying out individual samples suggests that daclizumab, which is used with cyclosporine, MMF and glucocorticoids, can increase mortality. In addition, studies with antibodies to the IL-2 receptor are limited, and the risk of lymphoproliferative diseases can not be ruled out.

Irradiation

Irradiation of a transplant, a local tissue site of the recipient or both of them can be used to treat cases of rejection of a kidney transplant, when another treatment (glucocorticoids, ATG) is ineffective. Total irradiation of the lymphatic system is at the stage of experimental development, but apparently, it safely suppresses cellular immunity primarily due to stimulation of suppressor T-lymphocytes, and later, perhaps, due to the clonal destruction of specific antigen-reactive cells.

Therapy of the future

At present, methods and preparations are being developed that induce antigen-specific tolerance of the graft without suppressing other types of immune response. Two strategies are promising: blockade of the T-cell costimulatory pathway using the cytotoxic T-lymphocyte-associated antigen 4 (CT1_A-4) -1d61 fusion protein; and the induction of chimerism (the coexistence of immune cells of the donor and recipient, in which the transplanted tissue is recognized as its own), using pre-transplantation without mieloablation (for example, cyclophosphamide, thymus irradiation, ATG, cyclosporin) to induce short-term depletion of the T-cell pool, with the subsequent tolerance in relation to transplants of solid organs from the same donor.