Title: Immunomodulation with FasL presenting PEG microgel achieves long term survival of allogeneic islets in the absence of immunosuppression in a non-human primate model chronic

Abstract

Introduction: The full potential of islet transplantation will only be realized by development of tolerogenic strategies that obviate the need for maintenance immunosuppressants. We are reporting a clinically relevant strategy that co transplantation of unmodified islets and SA-FasL-presenting immunomodulatory biomaterials achieved long term islets acceptance and glycemic control in the absence of chronic immunosuppression in an allogeneic diabetic non-human primate (NHP) model. Methods: Poly (ethylene glycol) [PEG]-based microgels presenting controlled densities of SA FasL are engineered. For experimental group, allogeneic unmodified islets from single donor were co-transplanted with SA-FasL-presenting microgels to the omentum of STZ-induced diabetic cynomolgus monkeys with Rapamycin as the only maintenance therapy for the first three months posttransplant. Recipients co transplanted islets with PEG microgels without SA-FasL served as controls. Animals were followed for six months to demonstrate that reproducible long-term grafts survival and tolerance can be achieved. Results: 4 experimental diabetic NHPs were co-transplanted with average 17K islet equivalents (IEQ)/Kg and SA-FasL-presenting microgel. Posttransplant each recipient promptly achieved excellent glycemic control with normal fasting BG during the 180- day designed study endpoint except one animal was electively terminated on day 147 posttransplant due to earlier grafts removal. IVGTTs performed at 3-month and 6-month post-transplant showed normal provocative glucose homeostasis, especially at the 6-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 50pmol/L respectively for all animals. After removal of the islets containing omentum, all the experimental animals returned to diabetic immediately. All 4 recipients demonstrated evidence of Treg expansion and reduction of effector memory T cells by flow cytometry; and donor hypo-responsiveness by in vitro ELISPOT and MLR. 3 Control group diabetic NHPs that co transplanted islets with non-FasL presenting microgel in the omentum and Rapamycin as the maintenance therapy achieved glycemic control less than 3 weeks, which is consistent with similar IS regimens in the literature and our previous studies. Recipient demonstrated no evidence of Treg expansion and donor hypo responsiveness during study period. Conclusions: Immunomodulation with SA FasL-presenting microgels results in long term allogeneic islet graft survival in a NHP model in the absence of chronic immunosuppression. SA FasL-presenting microgels as an off-the-shelf product presents a novel immunomodulatory approach with considerable translational potential for the treatment of type 1 diabetes.

Biography

Ji Lei is an Associate Immunologist and the Director of the Human Islet/Cell Isolation and Transplantation Special Service cGMP Facility at Massachusetts General Hospital. He also holds an Assistant Professor of Surgery position at Harvard Medical School. As a surgeon, he was formally educated and trained in medicine, medical research, and business administration at 4 universities. He has over 30 years of clinic practice and research experiences with more than 70 research papers contributions. His research focuses are on immuno-tolerance induction, immune modulation, immune-isolation, and innovations of technologies in the fields of pancreatic islet transplantation to treat diabetes and hepatocyte transplantation to treat liver function failure. His core research expertise is in field of nonhuman primate translational studies for biomaterials such as encapsulation, immunomodulation, and novel cells derived from stem cells for the treatment of diabetes.