Immunosuppressive therapy: Current limitations and future prospects

Summary

Immunosuppression is the cornerstone of clinical organ transplantation. The introduction of azathioprine (AZA) in 1962, followed by the empirical addition of corticosteroids (CS), ushered in the modern era of pharmacological immunosuppression for kidney transplantation. This therapeutic regimen displayed a slippery slope of insufficient effect, allowing rejection and graft loss or excessive effect with toxic, sometimes lethal side effects. Graft survival improved markedly with use of the T-cell-selective agent cyclosporine (CsA), allowing the successful transplantation of extrarenal organs as well. However, drug-induced toxicities preclude CsA use at optimally immunosuppressive drug concentrations. An alternative strategy to reduce CsA exposure and ameliorate toxicity substitutes anti-lymphocyte preparations during induction and/or combines CsA with other immunosuppressants (AZA/CS) for maintenance therapy. Unfortunately, the benefit of these empirical strategies has not been evaluated in a rigorous fashion. Additionally, concentration-controlled regimens are necessary to optimize transplant results, because of significant inter-individual variability in CsA pharmacokinetics. A variety of promising new immunosuppressants — FK-506, rapamycin, brequinar, RS61443, and a series of monoclonal antibodies — are under investigation. In order to expedite the process and ensure the safety of the transition from the laboratory into the clinic, a rigorous, standardized clinical trial methodology must be developed. Recent progress employing mathematical models to evaluate the effects of drug interactions, such as the median-effect analysis, may help to focus future studies. Finally, only controlled, randomized, blinded clinical trials can reliably establish the utility of new drugs and/or drug combinations. Because of the success of CsA-based regimens, large groups of patients must be entered to prevent Type I and Type II statistical errors, both of which ultimately harm the patient. Although this enterprise requires cooperation and discipline between transplant centers, adherence to these principles portends a bright future for clinical transplantation.