The evolving role of sirolimus in renal transplantation.
Sirolimus (rapamycin) is a macrolide antibiotic isolated from the fungus Streptomyces hygroscopicus 1 first identified in soil samples from Easter Island. Structurally similar to the calcineurin inhibitor (CNI) tacrolimus (Figure 1), it shares its potent immunosuppressive properties, but with a novel mechanism of action (Figure 2). Initial clinical trials have focussed on its use as adjunctive therapy, substituting for the anti-metabolite azathioprine. However, given that it lacks the nephrotoxicity of the CNIs (cyclosporin and tacrolimus), it has the potential to supplant these agents as baseline immunosuppressive therapy following renal transplantation, and offers the added potential benefit of promoting immunological tolerance. Figure 1. 
Structure of sirolimus. Sirolimus (rapamycin) is a macrocyclic lactone structurally similar to tacrolimus (FK506).





 Figure 2. 
Mechanism of action of sirolimus (rapamycin). CD4-positive T cells recognize a complex of class II MHC and peptide present on the surface of antigen-presenting cells (APCs). This results in signalling via the T cell receptor (TCR) and activation of calcineurin, a phosphatase. Calcineurin dephosphorylates NFAT (nuclear factor of activated T cells) facilitating its transfer into the nucleus where it acts as a transcription factor regulating IL-2 production. IL-2, and other cytokines, in turn promote further T-cell activation and proliferation, following interaction with its cell surface receptor (IL-2R). Of note, T-cell receptor engagement alone is insufficient to produce an immune response. Co-stimulatory signals (prototypically via CD28) are also necessary to produce and sustain a T-cell response. T-cell receptor engagement in the absence of co-stimulatory signals is thought to produce tolerance by inducing non-responsiveness to specific antigens and promoting apoptotic deletion of the activated cells (activation-induced cell death, AICD). Cyclosporin and tacrolimus (FK506) act by binding to their respective immunophilins (cyclophilin/FK-binding protein, FKBP-12) with the resultant complexes producing calcineurin inhibition. The net effect is blockade of IL-2 production, resulting in inhibition of T-cell activation. Sirolimus (SRL) also binds … 



Address correspondence to: Dr A.N Warrens, Department of Immunology, Commonwealth Building, Hammersmith Hospital, Ducane Road, London W12 0NN. e-mail: a.warrens{at}ic.ac.uk