Mechanism of Action of Immunosuppressive Drugs

Introduction

The most frequently used immunosuppressive drugs and their modes of action are briefly summarized below.

Corticosteroids

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.

Cytotoxic Drugs

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.

Antimetabolites

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.

Cyclosporine

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.