Section Review; Pulmonary-Allergy, Dermatological, Gastrointestinal & Arthritis: Recent developments with immunosuppressant macrolides: Tacrolimus and sirolimus

Abstract

Since the discovery and the clinical use of cyclosporin A (CsA), progress in immunosuppressive therapy has been rapid over the last decade and is expected to accelerate even more rapidly in the near future. The clinical and commercial success of CsA led other companies to screen fermentation products for immunosuppressive activity. One of the most potent compounds identified to date is FK506 (tacrolimus), which has a mode of action and toxicity profile similar to those of CsA. Another potent immunosuppressive identified in a similar manner is rapamycin (sirolimus). Both FK506 and rapamycin are macrolides and, although they present structural resemblance, they inhibit two distinct T-cell signalling pathways: T-cell activation and T-cell proliferation. CsA and tacrolimus act soon after Ca2+-de-pendent T-cell activation to prevent the synthesis of cytokines important for the perpetuation and amplification of the immune response. Sirolimus acts at a later stage to block the multiple effects of cytokines on immune cells, including the inhibition of interleukin-2-triggered T-cell proliferation. However, the antiproliferative actions of sirolimus are not restricted solely to effects on T- and B-cells; it also selectively inhibits the proliferation of growth factor-dependent and -independent non-immune cells.

Clinical experience has revealed that, in general, tacrolimus leads to lower rejection rates than CsA, and has a similar side-effect profile, primarily nephrotoxicity and neurotoxicity. Preclinical evaluation of sirolimus has not revealed any important adverse events in the animals tested, and clinical trials are currently underway in a few centres. Optimal therapy for both drugs requires careful monitoring of blood levels to maintain their concentrations within therapeutic ranges.