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 shown that targeting the CD28/CD80/CD86 and CD40/CD154 costimulatory pathways, by using LEA29Y and Chi220, prolongs allograft survival in rhesus macaques (Adams et al., J Immunol 2005). Based on these results, we investigated the effects of CTLA4Ig and 3A8, which likewise inhibit the CD28/CD80/CD86 and CD40/CD154 pathways, respectively. All recipients in this cohort had immediate allograft function with normalization of fasting blood sugars and prolonged allograft survival, proving costimulation blockade-based regimens continue to yield success in islet transplantation. After transitioning to a new diabetes induction model with the use of streptozocin, experiments began to determine the optimal islet mass and anatomic site for islet transplantation. One animal was transplanted with15,000IE/kg of allogeneic islets intramuscularly into the trapezius and latissimus dorsi muscles with moderate success. In this report period, no further islet mass or anatomic site experiments have been done due to the desire for a more optimal biologic immunosuppressive regimen. In search of a more clinically relevant, less toxic regimen, primates were transplanted allogeneic islets under cover of anti-LFA-1 monoclonal antibody-based therapy with very promising results. Anti-LFA-1 has proven to be a very potent immunosuppressant in our preclinical islet transplant model, making the case for its use in clinical trials. More promising though has been the recent use of a purely biologic regimen, anti-LFA-1 mAb and belatacept alone, resulting in immediate reversal of diabetes and islet survival 60 days. This biologic regimen promises to be a clinically relevant, tolerable regimen ideal for use in the optimization of islet mass and anatomic site for islet transplantation.