The impact of cyclosporine on the development of immunosuppressive therapy.

The first immunosuppressive regimens based on glucocorticoids and azathioprine were introduced in the early 1960s. However, many patients developed acute rejection, which required treatment with high doses of prednisolone. Leading to a high mortality due to opportunistic infection. Prior to 1985, our center used a regimen of prednisolone and azathioprine for 352 renal transplantations with 1-year graft and patient survival rates of 63.9% and 82.4%, respectively. Cyclosporine was introduced into clinical practice in 1978, enabling more effective control of acute rejection. In 1985, our center adopted a protocol consisting of prednisolone, azathioprine, and cyclosporine producing significantly increased 1-, 3-, and 5-year patient and graft survival rates for living-related and cadaveric renal transplants. Newer drug combinations, which are less toxic and more potent than cyclosporine based protocols, have further decreased acute rejection rates from 60% to approximately 10%. Still, graft loss continues to be a problem. We believe that the most recent strategy of combining monoclonal antibodies with less toxic agents, such as sirolimus and mycophenolate mofetil, may eventually replace calcineurin inhibitors. Such protocols would eliminate the side effects of calcineurin inhibitors, and possibly permit steroid-free maintenance therapy. The immunosuppressive therapy that is currently available is not ideal; the ability to convert patients to a state of permanent immunologic tolerance would minimize the need for these drugs. The new generation of agents that includes FTY 20, anti-sense oligonucleotides, and agents capable of blocking the costimulatory pathway of allorecognition may improve host tolerance.