Introduction

Clinical islet transplantation has relied almost exclusively on intraportal administration of pancreatic islets to the liver. However, this approach exposes transplanted islets to a suboptimal environment due to the immediate-blood-mediated inflammatory response, hypoxemia, and high levels of immunosuppressive drugs. Importantly, islets transplanted to the liver are not retrievable should undesirable side effects occur, such as the development of teratomas when stem cell-derived islets (SC-islet) are used as the source of the graft. While the omentum features an attractive extrahepatic alternative site due to its 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, full long-term euglycemia has not been achieved in either non-human primate (NHP) or human recipients to demonstrate its efficacy for clinical islet transplantation. We explored an approach in which allogeneic islets were transplanted onto the bioengineered omentum of three diabetic NHPs.

Methods

Naked allogeneic islets in a one-donor-one-recipient fashion were transplanted onto the omentum which is bioengineered with a plasma-thrombin biodegradable matrix of STZ-induced diabetic cynomolgus monkeys. A clinically relevant immunosuppressive regimen consisting of Thymo, Rituxan induction with Rapamycin only maintenance therapy is applied. Animals were followed for three months to ensure that reproducible long-term graft survival and function can be achieved by this method.

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. Posttransplant Insulin and C-peptide levels were comparable to that of naïve animals as well. All 3 recipients demonstrated evidence of donor hypo-responsiveness by in vitro ELISPOT and MLR assays during the period of normoglycemia.  Examination of the omentum at autopsy showed well preserved islet structures with strong insulin staining.  

Conclusions

Fully long-term euglycemia and insulin independence were achieved by implantation of islets onto the bioengineered omentum in one donor per each recipient fashion.  This study is the first report of a successful allogeneic islet transplantation 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 and translational as the omentum bioengineering approach and immunosuppressive regimen we use are clinically applicable.