New immunosuppressive agents for maintenance therapy in organ transplantation

Traditional cyclosporin-based immunosuppressive protocols are associated with relatively high incidences of early acute rejection and late graft loss due to chronic rejection. In addition, long-term immunosuppression with cyclosporin and corticosteroids has been associated with significant metabolic, infectious, malignant and cosmetic adverse effects. In the last decade, the goals of immunosuppression strategies have included not only short-term survival but also graft acceptance, with a low incidence of early acute rejection and minimal long-term toxicity. Tacrolimus and mycophenolate mofetil are 2 new immunosuppressive agents that have recently been approved for use. The mechanism of action and toxicity profile of tacrolimus are similar to that of cyclosporin. Tacrolimus reduces early acute rejection and is also effective in salvage of allografts with refractory rejection. A wide spectrum of adverse effects, including nephrotoxic, neurotoxic, gastrointestinal, metabolic and hematological effects, has been reported in association with tacrolimus but, unlike cyclosporin, this agent is not associated with hirsutism or gingival hyperplasia. Mycophenolate mofetil, an antimetabolite, has been effective in reducing early acute rejection and in treatment of refractory rejection when used in combination with cyclosporin instead of azathioprine. Its myelosuppressive and gastrointestinal toxicities are mild and reversible, but it may be associated with an increased risk of infections. Both agents permit early corticosteroid withdrawal. Other new immunosuppressive agents that act on different stages of the cell cycle but that have not yet been introduced for wide clinical use, including sirolimus (rapamycin), brequinar, mizoribine and gusperimus, are also discussed in this review.