Evolving role of sirolimus immunosuppression after organ transplantation

Abstract

Listen

Translate article

Sirolimus is a fermentation product similar in structure to the calcineurin inhibitor tacrolimus and the macrolide class of antibiotics. Sirolimus exerts its biologic effect through a distinct mechanism, inhibiting cyclin dependent signaling kinase(s) to prevent cell proliferation by G1-S phase cell cycle arrest. Evidence indicating synergy between calcineurin inhibitors and sirolimus provided the initial rationale for studying cyclosporine and tacrolimus dose minimization and corticosteroid free-immunosuppression. The potent antirejection properties observed in experimental systems led to studies demonstrating efficacy using sirolimus without calcineurin inhibitors. As the prototypic example of a novel class of immunosuppressants, sirolimus has demonstrated other biologic properties of possible relevance in transplantation, including anti-B and antimesenchymal cell effects. The latter properties have been the subject of recent investigations exploring sirolimus for preventing or ameliorating allograft arteriosclerosis. Additionally, sirolimus-associated antiproliferative properties have been shown to prevent tumor progression in several experimental models of malignancy. As with other immunosuppressants, sirolimus use has been associated with undesired biologic side effects. The pivotal clinical trials used full dose cyclosporine with sirolimus demonstrating reduced rejection rates, but sirolimus-treated patients sustained higher serum creatinine values. Sirolimus was also associated with serum cholesterol and triglyceride elevations, and reversible thrombocytopenia and leukopenia. Presumably a consequence of the antimesenchymal (fibroblasts, smooth muscle cells) properties, an increased incidence of lymphocele formation and delayed healing, particularly of complex wounds has also been suggested. Taken together, evidence indicates that sirolimus represents an important advance in immunosuppression after organ transplantation.