Targeting pathways of inflammation in islet allotransplantation post kidney transplantation using AAT

Isolated pancreatic islet transplantation holds potential as a minimally invasive approach to replenish the beta cell mass in type I diabetes. Recent data indicate that implementation of post Edmonton anti-rejection and anti-inflammation drug regimens resulted in markedly improved results of islet transplantation with long-term insulin independence approaching or equaling the rate in whole organ pancreas transplants at the five-year time point. Despite this success, a number of obstacles still impede achieving the full potential of islet transplantation, including: 1) the frequent need for infusions from more than one donor to achieve insulin independence, 2) early loss of a significant portion of transplanted islet mass, 3) gradual attrition of islet mass over time, and 4) the cost of the procedure. The current proposal seeks to evaluate a novel strategy to minimize early loss of islets and thus improve islet engraftment by administering the anti-inflammatory, immunomodulatory agent ?-1 antitrypsin (AAT; Aralast). AAT is a clinically available agent that is used to treat A1AT deficiency and which has demonstrated remarkable promise in both mouse studies and preclinical large animal experiments as a means to increase engraftment and promote long-term graft survival. We hypothesize that AAT induced increases in initial engrafted mass will enhance the rate single donor cure rates and reduce chronic attrition of islet mass prolonging insulin independence and improving the overall efficiency of the procedure. To test this thesis, we will conduct pilot studies in 3 patients receiving islet allotransplants post kidney transplants and assess engrafted islet mass. The results will be compared to already transplanted patients who have received islet transplants using a similar immunosuppressive and islet isolation protocol. The immunological impact of AAT administration will also be monitored.