CsA and FK506 are powerful suppressors of the immune system, most notably of T cells. They act at a point in activation that lies between receptor ligation and the transcription of early genes. Here, Stuart Schreiber and Gerald Crabtree review recent findings that indicate CsA and FK506 operate as prodrugs: they bind endogenous intracellular receptors, the immunophilins, and the resulting complex targets the protein phosphatase, calcineurin, to exert the immunosuppressive effect.

The clinical utility of cyclosporin A (CsA) and FKS06 stems from their ability to prevent graft rejection following organ transplantation. These drugs exert their major therapeutic effects by inhibiting T-cell activation. The repression of an early step in T-cell activation apparently leads to a failure to activate the transcription of early genes, such as those encoding the cytokines, which normally function in coordinating the various cells involved in the immune response. Thus, from a primary effect largely but not wholly confined to T cells, a wide variety of secondary effects are mediated, leading to profound and therapeutically useful immunosuppression.