Induction of islet allotolerance in nonhuman primates

Recent clinical trials have pioneered the successful use of a nonsteroidal immunosuppressive regimen and established a basis for application in a routine clinical setting. In this study, a single islet transplant was not sufficient to regulate blood glucose levels, and a second transplant became necessary. A similar observation was made in our macaque islet transplant study, where animals after the second transplantation have shown trends towards normoglycemia in the presence of mycophenolate mofetil. All five animals that received the second transplant have shown an initial rise in C peptide levels, which rapidly decreased as we tapered the MMF dose from 20 mg/kg BID to 5 mg/kg SID. Two animals of the five that were preconditioned with MMF one week prior to transplantation have shown significantly higher C peptide levels. We believe that it is very important to understand the relationship between the first graft failure and subsequent islet allograft success. Since graft success did not correlate with number of transplanted islets, the correction of blood glucose levels toward normoglycemia after the second transplantation suggests a mechanism by which the allotolerance to second transplant is facilitated by the first islet transplantation. These initial observations suggest approaches to "tolerize" the recipient to accept the second-transplant islets (a) through preconditioning the animal to improve the rate of success for the first transplant or (b) through tolerization to islets in the first transplant to facilitate better engraftment of the second-transplant islets.