*Purpose: In the current standard clinical transplant approach, islet cells are administered intravenously into the portal system where they lodge in the liver. This approach exposes transplanted islets to a suboptimal environment due to the immediate-blood-mediated inflammatory response, hypoxemia and high levels of immunosuppressive drugs. Furthermore, this technique often requires multiple transplants to gain a sufficient engrafted mass to secure euglycemia due to loss of the transplanted beta cell mass, poor islet survival and function. Because of the omentum’s rich blood supply, capacity to accommodate a large islet mass, convenient and minimal invasive route to implant and retrieve grafts, portal drainage and potential immune-privilege, this site may provide a suitable alternative site for islet transplantation. This approach can successfully reverse chemically induced diabetes in rat models and achieved insulin independence in 1 reported patient for up to 1 year but failed to cure diabetes in NHP models. We report a successful, clinically relevant islet transplantation model whereby allogenic islets are implanted in omental pouch and reverse diabetes long-term in diabetic nonhuman primate (NHP) recipients.

*Methods: As part of a JDRF sponsored study, allogeneic naked islets from single donor were transplanted to the omentum of STZ-induced diabetic cynomolgus monkeys applying a clinically relevant immunosuppressive regimen consists of Thymo (5mg/kgx4), Rituxan (20mg/kgx2) induction with Rapamycin only maintenance therapy. Animals were followed for three months to ensure that reproducible long-term graft survival and function can be achieved in this site.

*Results: 3 diabetic NHPs were transplanted with 98,400-105,000 islet equivalents (IEQs) and each promptly achieved normoglycemia. Glycemic control and insulin independence were maintained for the entire 90 days of study duration except one animal was electively terminated on day 48 posttransplant due to a study unrelated complication. IVGTTs performed at 1- and 3-month post-transplant showed normal provocative glucose homeostasis, especially at the 3-month time point where blood glucose dynamics were as robust as the normal healthy animal. Insulin and C-peptide were greater than 1.5mU/L and 2.0 ng/mL respectively for all animals. All 3 recipients demonstrated evidence of Treg expansion by flow cytometry and donor hyporesponsiveness by in vitro ELISPOT assay during the period of normoglycemia. Examination of the omentum at autopsy showed well preserved islet structures with strong insulin staining, and only rare lymphocytes infiltration.

*Conclusions: Fully long-term euglycemia and insulin independence were achieved by implantation of islets in the omental pouch. This study is the first report of a successful transplantation of single donor islets to the omentum in NHPs, which is a highly relevant pre-clinical animal model to develop strategies for beta cell replacement including stem cell derived beta cell and bio-engineered cells. Our protocol is attractive as the omentum pouch and immunosuppressive regimen we use are clinically applicable.

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