The impact of immunosuppressive drugs on the analysis of T-cell activation

The discovery of the immunosuppressive properties of cyclosporin A (CSA) an d its successful utilisation in organ transplantation was a milestone in cl inics. CSA has revolutionised transplantation both in term of efficiency an d quality-of-life of the patient. In addition, the analysis of the mode of action of CSA has been rewarding in the understanding the mechanisms leadin g to T lymphocytes activation. CSA binds to a family of cytosolic receptors , the cyclophilins, a highly conserved family of proteins. Once this comple x is formed, a third protein, the calcineurin, is recruited. The calcineuri n, a calcium-dependent phosphatase, loose its activity when complexed. Deph osphorylation of NFAT, a substrate of calcineurin is a mandatory step for i ts translocation to the nucleus where NFAT acts as a transactivator involve d in the regulation of the genes encoding many cytokines. CSA preventing NF AT dephosphorylation blocks cytokine production this in turn allowing for a better engrafting. The resolution of the tertiary structure of CSA alone o r complexed with cyclophilin and calcineurin has important implication in t he modelling of new drugs devoid of its side effects. Indeed, the high inci dence of cancer is one of the main problems linked to CSA utilisation. Rece nt data suggest that CSA may promote cancer inducing the transcription of t he gene encoding transforming growth factor beta. Other molecules sharing w ith CSA its immunosuppressive activity were later described. Some of them, as FK506, have the some mode of action; others, as rapamycin, mycophenolate mofetil or leflunomide, act at different steps of T cell activation.