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.