STRATEGIES FOR LARGE SCALE ISLET REPLACEMENT

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We recently showed that targeting the CD28/CD80/CD86 and CD40/CD154 costimulatory pathways, by using LEA29Y and Chi220, prolongs allograft survival in rhesus macaques. Based on these results, we investigated several alternative drug regimens as well as alternative methods of diabetes induction. While we traditionally use the duodenal-sparing pancreatectomy, streptozotocin is used in other models to produce diabetes. Streptozotocin has several advantages over pancreatectomy including the avoidence of a major operation with its associated risks and preservation of the exocrine function of the pancreas. Three animals underwent diabetes induction with streptozotocin and subsequent alloislet transplant under cover of a CTLA4Ig and 3A8 costimulation blockade-based regimen. All recipients in this cohort have had immediate allograft function with normalization of fasting blood sugars by day 1 post-transplant. Studies have begun to determine the optimal anatomic site for islet transplantation. Focus has begun on an omental pouch to evaluate multiple anatomic locations to determine the optimal anatomic site for islet transplant.