The most frequently used immunosuppressive drugs and their modes of action are briefly summarized below.
This group of drugs has potent and direct anti-inflammatory effects on immunocompetent cells. Corticosteroids inhibit lymphocyte proliferation and cell-mediated immune responses more severely than they inhibit antibody responses. T helper cells, eosinophils, and monocytes are reduced in peripheral blood. Corticosteroids down-regulate cytokine gene expression through interference with transcription regulation. By inhibition of phospholipase A2, synthesis of inflammatory arachidonic acid metabolites (prostaglandins and leukotrienes) is suppressed. Corticosteroids have been shown to block the activation of T cells by interleukin-1 (IL-1) derived from macrophages. They also inhibit the expression of class II histocompatibility antigens on the macrophage surface, thereby interfering with presentation of antigen to T cells. Cumulatively, these cellular changes result in reduced inflammatory responses.
The most frequently used cytotoxic drugs are the anti-metabolites (see below) and cyclophosphamide. Cyclophosphamide is an alkylating agent that damages cells by cross-linking DNA. Although this cycle-specific drug is most effective in killing cells going through the mitotic cycle, it can also cause intermitotic cell injury and death. Cyclophosphamide can inhibit both T and B cell immunity as well as inflammation. Azathioprine and cyclophosphamide are effective inhibitors of the production of serum antibodies.
The most commonly used antimetabolites are methotrexate, an inhibitor of folic acid synthesis, and azathioprine, a structural analog of mercaptopurine and an antagonist of purine synthesis. Azathioprine is a phase-specific drug that kills rapidly replicating cells. It inhibits proliferation of both T and B cells as well as macrophages. Methotrexate inhibits rapidly proliferating cells in S phase and suppresses both cell-mediated and humoral immunity as well as inflammation. Without immunosuppression, the incidence of graft-versus-host disease after allogeneic HPC transplant is almost 100%; this can be reduced to 20-30% with immunosuppressive therapy, especially the combination of methotrexate and cyclosporine, in addition to corticosteroids. Cyclosporine prevents T cell activation, while methotrexate inhibits the function of T cells that are already activated.
This cyclic polypeptide derived from a fungus is used as an immunosuppressive drug in organ transplant recipients. Cyclosporine binds to cyclophilin, a cytoplasmic protein, thereby interfering with calcium-dependent events including secretion of interleukin-2 (IL-2) by T lymphocytes. Since IL-2 is necessary for T cell replication, this drug is a potent inhibitor of T cell proliferation and thereby inhibits T cell-mediated immune responses. Little effect has been shown on direct B cell immune responses or on inflammation. Its toxic effects are primarily on renal and, to a lesser extent, hepatic function. In addition to methotrexate, methylprednisolone has also been utilized with cyclosporine to treat graft-versus-host disease, though T cell-directed immunotoxins have not proved to be of any benefit. A recently developed microemulsion formulation offers improved oral bioavailability, safety, and efficacy.
Like cyclosporine, tacrolimus also inhibits calcineurin-dependent phosphorylation of nuclear transcription factors, thereby inhibiting T cell activation and subsequent production of IL-2 and interferon-?. Sirolimus, another fungi-derived macrolide, also blocks antigen- or cytokine-induced cellular immune responses. Both are approved for use in kidney and liver transplantation as primary immunosuppressive agents, and as rescue therapy, but may also be used to prevent graft-versus-host disease.
Tacrolimus is approximately 100 times more potent than cyclosporine. Rates of graft-versus-host disease are lower for tacrolimus-based regimens. Tacrolimus appears to be at least as effective as cyclosporine, possibly better as prophylaxis of acute rejection. The major toxicities include hyperglycemia, nephrotoxicity, and neurotoxicity. Topical formulations are well tolerated and have shown efficacy in the treatment of atopic dermatitis and allergic contact dermatitis.
Sirolimus has been used as an add-on therapy to minimize the dosages of cyclosporine or prednisone and their subsequent toxicities. In particular, sirolimus added to other calcineurin antagonists appears to be less commonly associated with immunosuppression-induced neoplasms or lymphoproliferative diseases.
Mycophenolate mofetil is used primarily as an adjunctive agent in kidney transplantation. By blocking lymphocyte production of guanine nucleotides, it inhibits T and B lymphocyte proliferation. Its use in combination with cyclosporine or tacrolimus has led to a lower incidence of acute allograft rejection, reducing the need for high-dose corticosteroids or OKT3 (muromonab-CD3).
Humanized Anti-Interleukin-2 Receptor Antibody
A humanized monoclonal antibody directed to the low-affinity IL-2 receptor is approved for use in kidney transplantation. This antibody, administered for 8 weeks following the transplant, when added to standard immunosuppressive therapy, results in a reduction of the incidence of acute graft rejection to about 25%. Alternatively, it may be used as an induction agent. Although the incidence of acute rejection is not substantially lower than that of other combinations of immunosuppressive agents, there appears to be a lower incidence and severity of side effects compared with antilymphocyte alternatives.
A murine monoclonal antibody, muromonab-CD3, is directed against human CD3, the T cell receptor. Indicated for acute graft rejection refractory to corticosteroids, large doses of the drug purge T cells from the systemic circulation. The drug has numerous side effects related to the release of cytokines, including fever, myalgias, dyspnea, and aseptic meningitis, and has also been associated with increased susceptibility to cytomegalovirus infection. Most patients are limited to a single course of therapy since recurrent courses may be associated with the production of neutralizing antibodies or posttransplant lymphoproliferative disease.
Revision date: July 7, 2011
Last revised: by Andrew G. Epstein, M.D.