Immunosuppression in Pediatric Heart Transplantation: 2003 and Beyond

Advances in immunosuppressive therapy have contributed to the improved long-term survival of pediatric heart transplant recipients over the past two decades. The introduction of cyclosporine in the early 1980s (the first oral agent to selectively target T-lymphocyte pathways) led to a dramatic reduction in acute rejection rates and improved graft and patient survival. A combination of cyclosporine, azathioprine, and corticosteroids ("triple therapy") became the standard of care for pediatric and adult heart transplantation. The introduction of several new agents in the past decade has resulted in an almost infinite number of potential immunosuppressive regimens, none of which have been (or are likely to be) tested in randomized clinical trials in children. Tacrolimus is replacing cyclosporine as the primary calcineurin inhibitor in many programs. Mycophenolate mofetil, despite its increased cost, is likely to replace azathioprine as the adjunctive antimetabolite of choice in heart transplantation. Furthermore, target of rapamycin inhibitors, such as sirolimus, will likely be used in lieu of antimetabolite agents if their known myointimal antiproliferative effects are demonstrated to reduce or prevent graft vasculopathy (chronic rejection) in humans. With the availability of more potent immunosuppressive agents, early steroid withdrawal or complete steroid avoidance will become the standard of care in most pediatric transplant programs. Complete avoidance of steroids can be facilitated by the use of induction therapy with polyclonal anti-T-cell antibodies (eg, rabbit antithymocyte globulin ) or with the use of nondepleting antibodies that block the interleukin-2 receptor (eg, basiliximab, daclizumab). All these agents appear to have a good safety profile and are likely to lead to a resurgence of interest in induction therapy as a strategy to avoid chronic use of corticosteroids in children. As the elucidation of immunosuppressive pathways continues to advance, many newer immunosuppressive agents will be developed that target specific critical pathways in the immune response to the allograft. These advances should lead to more focused immunosuppression, greater drug synergism, reduction in the doses of individual agents, steroid-sparing regimens, and reduction in end-organ toxicities. The ultimate goal will be to define a perioperative therapeutic regimen that will result in a state of " transplantation tolerance," in which the patient will indefinitely accept their allograft without the need for chronic immunosuppressive therapy.