New immunosuppressive drugs in organ transplantation

Abstract

An examination of the mechanisms by which four new immunosuppressive drugs--rapamycin, mizoribine, mycophenolate mofetil, and 15-deoxyspergualin--exert their effects reveals three major categories. Rapamycin binds to an intracellular immunophilin. The resulting drug-immunophilin complex inhibits the action of cytokines, thus blocking the activation and proliferation of T cells. Mizoribine and mycophenolate mofetil are antimetabolites that inhibit a key enzyme in the de novo purine biosynthetic pathway. As a result, the proliferation of T cells and B cells is inhibited selectively compared with that of nonlymphoid cells because the salvage pathway is unavailable to lymphocytes. Finally, 15-deoxyspergualin has a unique mechanism of action, which includes suppressive effects on macrophage function, the induction of cytolytic T cells, B-cell reactivity, and antibody responses. The demonstrated synergism among certain immunosuppressants allows reduction in the dose of each agent to minimize the individual toxicities. As more of these new agents become available, it is likely that azathioprine will be replaced, and it may be possible to eliminate the need for long-term maintenance steroid therapy.