LONG-TERM INTRAHEPATIC ISLET ALLOGRAFT SURVIVAL IN NON-HUMAN PRIMATES TREATED WITH ANTI-CD154 MONOTHERAPY

Abstract

32 Conventional immunosuppressive drugs are known to impair normal islet function, increase susceptibility to infection and malignancy, stunt normal growth and development, and result in direct organ toxicity. In addition, activation of macrophages and endothelial cells as a result of intrahepatic islet transplantation can lead to inflammatory events that have an adverse effect on islet engraftment and function. We reasoned that reported effects of anti-CD154 treatment on autoimmunity, alloreactivity, and inflammatory events mediated by macrophages and endothelial cells, made it an ideal agent for the prevention of islet allograft failure. We have previously demonstrated that anti-CD154 is not diabetogenic. Utilizing a rhesus monkey model of pancreatectomy-induced diabetes, humanized anti-CD154 (hu5c8) was administered I.V. on POD −1, 0, 3, 10, and 18 (induction therapy, POD 0 = day of pancreatectomy and islet cell transplant), and maintenance therapy was administered every 28 days, beginning on POD 28. Engraftment and long-term survival and function (insulin independence) was obtained in 6/6 monkeys (POD >39, >160, >180, >319, >332, >404). In striking contrast, a control, non-treated monkey was insulin independent subsequent to islet transplantation but rejected the graft on POD 6. One additional monkey that was given a marginal islet mass, and never became insulin independent, was given a second transplant and has been insulin independent for >276 days. The results of intravenous glucose tolerance testing revealed that first phase insulin release (FPIR) in the first few months post-transplant was dependent on the mass of islets transplanted. Improved FPIR was observed in all monkeys subsequent to the first 3-4 months post-islet cell transplant, thus suggesting that revascularization and engraftment take approximately 100 days in this model. All monkeys have maintained FPIR throughout the follow-up period. All anti-CD154 treated recipients were positive to donor cells in mixed leukocyte cultures pre-transplant, and all became specifically non-responsive to donor cells, while retaining reactivity to 3rd party cells and mitogen, post-transplant. Anti-donor alloantibody was detected in 1/4 monkeys tested. These unprecedented results, obtained in the absence of the deleterious effects of conventional immunosuppressive drugs, suggest that anti-CD154 (hu5c8) may be an ideal gent for clinical islet cell transplantation.