Sirolimus (rapamycin) in clinical transplantation

Abstract

Sirolimus (rapamycin) is a newly licensed immunosuppressant that ushers in a new era of immunosuppression. Unlike tacrolimus and cyclosporin, sirolimus is not a calcineurin inhibitor (CNI) and shares few side effects associated with CNI therapy. Most importantly, it is not nephrotoxic, neurotoxic, or diabetogenic. Sirolimus binds to the 12-kd member of the FK506 binding protein immunophilin family; this complex interacts with the target of rapamycin, a key step in coreceptor- and cytokine-mediated stimulation, resulting in growth arrest late in the G-phase. Thus, sirolimus does not inhibit cytokine gene transduction like cyclosporin, but acts later in the cell cycle to inhibit cytokine-stimulated proliferation of T cells. Its adverse effects include bone marrow suppression, increased serum lipid levels, and impaired wound healing. It is synergistic with cyclosporin and tacrolimus and has been shown to be as potent as cyclosporin in the immunosuppression of renal allografts. Its principal role likely will be in combination with CNIs in the early treatment phase after transplantation, possibly with a CD25 monoclonal antibody and no steroids, and as the principal agent for maintenance therapy after CNI withdrawal. Everolimus, a derivative of sirolimus, shares many of the properties of sirolimus and is being developed along similar lines.