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 have recently shown 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 are currently investigating several alternative drug regimens as well as alternative methods of diabetes induction. In an effort to expand our ability to investigate pharmacologic agents, we are also examining the effects of CTLA4Ig and 3A8, which likewise inhibit the CD28/CD80/CD86 and CD40/CD154 pathways, respectively. 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. In August of 2006, 11 specific pathogen-free macaques were obtained to be used in part for this project. After three months in quarantine, potential recipients were MHC typed and underwent ear stick training for blood glucose monitoring. Three animals have undergone diabetes induction with streptozotocin and subsequent alloislet transplant under cover of a CTLA4Ig and 3A8 cotimulation blockade-based regimen. All recipeints in this cohort have had immediate allograft function with normalization of fasting blood sugars by day 1 post-transplant. We are currently planning to administer streptozotocin to additional animals and initiate experiments examining different anatomic sites such as the omentum, the muscle, and the subcapsular space of the kidney for alloislet cell transplant.