Sirolimus and islet transplants.

IMMUNOSUPPRESSION is a critical determinant of the success of islet transplants. Tailoring immunosuppression to the specific setting of marginal mass islet cell transplants in autoimmune type 1 diabetic recipients would likely increase the safety, success rate, and applicability of such transplants. Tailored immunosuppression would ideally inhibit antigen-independent innate immune responses during the engraftment of transplanted islets, control alloimmune responses, and thwart autoimmune responses without diabetogenic and nephrotoxic side effects. Rejectionfree protocols need to be administered until markers of imminent islet rejection are validated or until robust function of a dysfunctional graft is restored. Sirolimus is a macrocyclic lactone with potent immunosuppressive properties. Its mechanism of action involves the blockade of IL-2 and other T-cell growth factor-mediated signal transduction and the inhibition of cell cycle progression. Sirolimus is conceivably the single most important contribution to the immunosuppressive armamentarium in islet transplantation. The immunosuppressive synergism between sirolimus and cyclosporin A (CsA) markedly reduces the incidence of solid organ and islet allograft rejection; it also enables steroids to be avoided and CsA doses to be profoundly reduced. In vitro studies suggested competitive inhibition between sirolimus and tacrolimus. Synergism between those two drugs was demonstrated in rat transplant models. The synergism between sirolimus (and other mammalian targets of rapamycin antagonists) and sphingosine 1-phosphate receptor agonists enables both steroids and calcineurin inhibitors to be avoided, thereby protecting allografts from rejection as well as from diabetogenic and nephrotoxic side effects. The synergism between sirolimus and selective blockers of costimulatory pathways helps induce immunologic tolerance and may, in the future, facilitate minimization or discontinuation of maintenance immunosuppression. The distinctive profile of sirolimus suggests an important role for it as an immunosuppressive and tolerogenic agent for diabetic recipients of islet transplants. Studies of the tolerogenic potential of sirolimus have been performed predominantly in cardiac and islet transplant models in mice. Sirolimus was used at a dose of 0.2 mg/kg/d intraperitoneally (IP) daily for the first 3 days, then every other day until the advent of hyperglycemia. It markedly prolonged the survival of islet allografts across a complete major histocompatibility barrier in interleukin (IL)-2 / and IL-4 / double knockout mice. Thus, sirolimus blocks T-cell growth factor signals beyond IL-2 and IL-4, especially IL-7 and IL-15; these rapamycin-sensitive T-cell growth factor signals are critical in the execution of islet allograft rejection. Combined costimulatory blockade (anti-CD154 monoclonal antibody and CTLA4-Ig) and sirolimus monotherapy 0.2 mg/kg/d IP on days 0, 1, 2, then every other day through day 14 posttransplant both facilitated indefinite survival of cardiac allografts in the Balb/c to C3H/He strain combination. Adding CsA, but not sirolimus, to treatment with anti-CD154 monoclonal antibody and CTLA4-Ig blocked the capacity of costimulatory blockade to produce permanent engraftment. Subsequently, islet transplant experiments were conducted in IL-2-deficient mice treated with sirolimus, and cardiac allograft transplant experiments in Bcl-XL transgenic mice treated with costimulatory blockade. Those experiments assessed the importance of alloreactive T-cell pool size, and more specifically activated-induced cell death of alloreactive T cells (in peripheral tolerance induction). They confirmed the hypothesis that sirolimus blocks the proliferative component of IL-2 signaling but does not inhibit priming of activation-induced cell death. They also demonstrated that deletion of activated T cells, through activation-induced cell death or growth factor withdrawal, is necessary to achieve peripheral tolerance across major histocompatibility barriers. The efficacy of sirolimus in preventing spontaneous and recurrent autoimmune diabetes has been studied in NOD mice, a clinically relevant model of autoimmune type 1 diabetes. Sirolimus was administered per os (PO) 3 times per week from 8 to 10 weeks of age; it prevented onset of autoimmune diabetes in 90% of NOD mice at a dose of 0.6