Treatment of Acute Rejection

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Corticosteroids are the first choice of treatment in acute rejection episodes. In cases where corticosteroids do not suppress acute attacks of rejection, the drugs used in induction therapy (ATG and OKT3) or maintenance therapy (tacrolimus and sirolimus) can be used. Topical corticosteroids and topical tacrolimus have successfully treated rejection in recipients of composite tissue grafts.26

Calcineurin Inhibitors (Cyclosporine A and FK-506)

Calcineurin is a phosphatase that is important for IL-2 gene transcription and release by T cells. Phosphorylation and dephosphorylation of specific proteins help regulate cytokine production in T cells. Both CsA and tacrolimus are prodrugs; they need to form a complex with cellular proteins called "immunophilins" before exerting their effects. Cyclosporine A binds to cyclophilin, whereas tacrolimus binds to FK-binding proteins. After the drugs are bound, they render the calcineurin complex inactive, preventing subsequent gene transcription of IL-2, thereby reducing the production of IL-2, a key cytokine for T-cell expansion, and of other cytokines.27

Cyclosporine A is a metabolite extracted from Trichoderma polysporum fungus. Cyclosporine A is highly specific for T cells and inhibits the activation of both CD4+ and CD8+. The effects of CsA in suppressing IL-2 production can be reversed by discontinuing the drug. The effect of CsA in blocking IL-2 release can be increased when used in combination with corticosteroids.26 28

Tacrolimus (FK-506) is a metabolite of an acti-nomycete, Streptomyces tsukubaensis, and is an effective alternative to cyclosporine. The structure of tacrolimus is different from that of CsA, and the mechanism of action is similar to that of cyclosporine. In vitro, tacrolimus appears to be 100 times more potent than CsA.29 Tacrolimus suppresses transcription of cytokines IL-2, IL-3, IL-4, IL-5, IFN-y, and TNF-a, as well as granulocyte macrophage colony stimulating factor.30

Both tacrolimus and CsA have similar renal and hepatic toxicities, but they differ in other toxic side effects. Patients treated with tacrolimus have a higher incidence of diabetes mellitus but a lower incidence of hypertension, hyper-lipidemia, and hirsutism.31 Tacrolimus is more potent than CsA in enhancing peripheral nerve regeneration and is therefore commonly used in human hand transplantation.32

Sirolimus (TOR Inhibitor)

Sirolimus (rapamycin) is structurally similar to tacrolimus and is extracted from the actino-mycete Streptomyces hygroscopicus. Sirolimus, like tacrolimus, binds to FK-binding protein-12, but unlike tacrolimus, it does not inhibit calcineurin phosphatase. Sirolimus blocks calcium-independent events during the G1 phase. Its immunosuppressive effect is by inhibiting TOR (target of rapamycin), which is an important enzyme in T-cell proliferation. TOR inhibitor, unlike calcineurin inhibitors, fails to interfere in the early events after T-cell activation. However, it overcomes other CsA-resistant pathways in T-cell and B-cell stimulation. Therefore, it inhibits the proliferation and maturation of B cells, which leads to extreme depression of host alloantibodies after allografting in a sensitized host.30

Adding sirolimus to combination regimens has allowed the dose of calcineurin inhibitors to be reduced, thus decreasing the nephrotoxicity associated with calcineurin inhibitors without decreasing graft survival.33 The main side effects of sirolimus are hypercholesterolemia, leukopenia, and thrombocytopenia; and, unlike calcineurin inhibitors, hypertension, nephrotoxicity, and hepatotoxicity are not common.26

Corticosteroids

Corticosteroids are nonspecific antiinflammatory agents that inhibit cytokine production by T cells and macrophages. In the initial phase of transplantation, they affect cytokine gene transcription and inhibit the secretion of several important cytokines, such as IL-1, IL-2, IL-6, TNF-P, and IFN-y, which are important in inflammatory reactions.

Corticosteroids were originally used to treat acute episodes of rejection in patients on aza-thioprine maintenance therapy. Currently, lower doses of corticosteroids are used in combination with other immunosuppressive agents or in short courses of high doses to treat acute rejection. Corticosteroids are also used to treat graft-versus-host disease after bone marrow transplantation and to minimize hypersensitivity reactions caused by induction immunosuppressants, such as monoclonal antibodies and antithymocyte globulin.26

The major adverse effects of high doses of corticosteroids are myopathy, diabetes, weight gain, fracture, peptic ulcers, gastrointestinal bleeding, opportunistic infections, and poor wound healing.

Antiproliferative Agents

Azathioprine, a purine analogue, has been used clinically since 1963. It changes in the liver to 6-mercaptopurine, then enters the cell to be converted to 6-mercaptopurine ribonucleotide, which resembles inosine monophosphate. This structural resemblance interferes with the cellular synthesis of DNA, RNA, and other cofac-tors. It acts early during the proliferative cycle of effector T-cell and B-cell clones. Recently, it has been replaced by MMF, which is more effective during the first 1 to 3 years after transplant. The major toxic side effects of azathioprine are bone marrow suppression, hepatotoxicity, and increased risk of malignancy.

The immunosuppressive activity of MMF is through inhibition of the purine synthesis pathway. It is a potent, reversible, noncompetitive inhibitor of inosine monophosphate dehydrogenase. Inosine monophosphate dehydrogenase is an essential enzyme for DNA synthesis in both T cells and B cells; thus MMF selectively blocks proliferation of T cells and suppresses antibody formation by B cells, sparing bone marrow and parenchymal cells, which rely more on the salvage pathway for purine synthesis.34

The side effects of MMF include diarrhea, esophagitis, and gastritis. The risk of leukopenia and opportunistic infections is similar in both MMF and azathioprine.26

Interleukin-2 Receptor Antagonists

The IL-2 receptor is a complex of several transmembrane polypeptide chains. Daclizumab (Zenapax) and basÛiximab (Simulect) are specific monoclonal antibodies that bind to the alpha chain of IL-2 receptors. The clinical use of these agents was associated with no major side effects, such as malignancy or opportunistic infections, when compared to placebo.35

Lymphocyte-Depleting Agents

Anti-CD3 antibody (OKT3) is a mouse-derived monoclonal antibody that binds to the CD3 glycoprotein on the T-cell surface, preventing antigen binding to the antigen recognition complex and blocking cell-mediated cytotoxicity. The side effects of OKT3 range from a mild flulike illness to a life-threatening shocklike reaction (cytokine release syndrome), encephalopathy, nephropathy, and hypotension. Cytokine release syndrome can be minimized by high doses of steroids a few hours before administration of OKT3.36

Antithymocyte globulin (ATG) is prepared from hyperimmune serum of horses and rabbits that were immunized with human thymic lymphocytes. ATG works by binding to the surface of T cells and depleting both circulating T cells and those within lymphoid organs. Polyclonal ATG causes lymphocyte depletion by complement-dependent lysis, opsonization, and apoptosis, and markedly affects other T-cell receptors by down-

regulation or binding.26 The main side effects of ATG are flushing, fever, anaphylaxis, and serum sickness. Other toxic effects include phlebitis, leukopenia, thrombocytopenia, and nephritis.

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