Long-term survival and function of intrahepatic islet allografts in baboons treated with humanized anti-CD154

Clinical islet cell transplantation has resulted in insulin independence in a limited number of cases. Rejection, recurrence of autoimmunity, and impa irment of normal islet function by conventional immunosuppressive drugs, e. g., steroids, tacrolimus, and cyclosporin A, may all contribute to islet al lograft loss. Furthermore, intraportal infusion of allogeneic islets result s in the activation of intrahepatic macrophages and endothelial cells, foll owed by production of proinflammatory mediators that can contribute to isle t primary nonfunction. We reasoned that the beneficial effects of anti-CD15 4 treatment on autoimmunity, alloreactivity, and proinflammatory events med iated by macrophages and endothelial cells made it an ideal agent for the p revention of islet allograft failure. In this study, a nonhuman primate mod el (Papio hamadryas) was used to assess the effect of humanized anti-CD154 (hu5c8) on allogeneic islet engraftment and function. Nonimmunosuppressed a nd tacrolimus-treated recipients were insulin independent posttransplant, b ut rejected their islet allografts in 8 days. Engraftment and insulin indep endence were achieved in seven of seven baboon recipients of anti-CD154 ind uction therapy administered on days -1, 3, and 10 relative to the islet tra nsplant. Three of three baboons treated with 20 mg/kg anti-CD154 induction therapy experienced delayed rejection episodes, first detected by elevation s in postprandial blood glucose levels, on postoperative day (POD) 31 for o ne and on POD 58 for the other two. Re-treatment with three doses of anti-C D154 resulted in reversal of rejection in all three animals and in a return to normoglycemia and insulin independence in two of three baboons. It was possible to reverse multiple episodes of rejection with this approach. A lo ss of functional islet mass, as detected by reduced first-phase insulin rel ease in response to intravenous glucose tolerance testing, was observed aft er each episode of rejection. One of two baboons treated with 10 mg/kg indu ction therapy became insulin independent posttransplant but rejected the is let graft on POD 10; the other animal experienced a reversible rejection ep isode on POD 58 and remained insulin independent and normoglycemic until PO D 264. Two additional baboon recipients of allogeneic islets and donor bone marrow (infused on PODs 5 and 11) were treated with induction therapy (POD s -1, 3, 10), followed by initiation of monthly maintenance therapy (for a period of 6 months) on POD 28. Rejection-free graft survival and insulin in dependence was maintained for 114 and 238 days, with preservation of functi onal islet mass observed in the absence of rejection. Prevention and revers al of rejection, in the absence of the deleterious effects associated With the use of conventional immunosuppressive drugs, make anti-CD154 a unique a gent for further study-in islet cell transplantation.