An update in transplant immunosuppressive therapy.

As we enter the millennium, the most widely acknowledged advancement in transplantation has been the development of more selective and potent immunosuppressive agents. In the early period of transplantation, the selection of maintenance immunosuppression was limited to the combination of azathioprine and corticosteroids. Unfortunately, these agents were relatively non-specific and ineffective and carried the risk of a multitude of side effects. The major clinical concerns at that time were the prevention of acute rejection and improvement in patient and graft outcomes, since expected patient survival post-transplant was low. The development of cyclosporine in the 1970s marked the first application of T-cell selective immunosuppressive therapy. The widespread clinical application of this agent in the 1980s significantly improved transplant outcomes and, depending on the specific organ and donor source, graft survival in the order of 85-90% at one year became commonplace. The last decade has built on the foundations of T-cell targeted immunosuppression with the introduction of tacrolimus, mycophenolate mofetil, rapamycin and new polyclonal and monoclonal antibodies directed at specific receptors (IL-2 receptor) on activated lymphocytes. (Table 1) These agents have been used in various combinations with the goal of achieving maximal immunosuppressive potency with minimal side effects. It is now commonplace to have rates of acute rejection less than 10% (Table 2), verifying the synergistic interactions of these agents. The outstanding results that are achievable with these newer medications makes it difficult to select a protocol based solely on efficacy data. The goals that define immunosuppressive therapy have shifted toward reducing maintenance immunosuppression and minimizing side effects. Furthermore, more emphasis is now placed on choosing immunosuppressive regimens tailored to fit the unique characteristics of the individual transplant recipient. The purpose of this article is to review these newer agents, their mechanisms of action and side effects, examine the choices that currently exist for immunosuppression, and finally discuss the potential hazards of their long-term use.