Cyclosporine: the agent and its actions

The serendipitous discovery of a new species of fungi T inflatum Gams coupled with the diligent investigations of Borel to dissect the immunosuppressive action of CsA have yielded a new reagent of compelling therapeutic moment. Due to its relatively specific inhibition of lymphokine generation by T helper cells, the drug displays relatively high therapeutic efficacy for the immune system. The major obstacle to almost uniform success is drug-induced nephrotoxicity, which not only occurs frequently but also is discerned with difficulty from allograft rejection. Nephrotoxicity may occur in the absence of toxic CsA drug levels, and therefore cannot be totally excluded by presently available tools, probably due to synergistic injuries to the allograft by drugs, donor ischemia, procurement injury, rejection, and so forth. Although present data and likely hypotheses suggest that immunosuppressive and nephrotoxic effects are closely correlated, careful chemical dissection of the differential immunosuppressive and toxic activities of CsA metabolites and/or structural variants may afford new approaches to improve the therapeutic window for effective CsA use.