The impact of cell surface PEGylation and short-course immunotherapy on islet graft survival in an allogeneic murine model

Abstract

Islet transplantation is a promising therapy for Type 1 diabetes mellitus; however, host inflammatory and immune responses lead to islet dysfunction and destruction, despite potent systemic immunosuppression. Grafting of poly(ethylene glycol) (PEG) to the periphery of cells or tissues can mitigate inflammation and immune recognition via generation of a steric barrier. Herein, we sought to evaluate the complementary impact of islet PEGylation with a short-course immunotherapy on the survival of fully-MHC mismatched islet allografts (DBA/2 islets into diabetic C57BL/6J recipients). Anti-Lymphocyte Function-associated Antigen 1 (LFA-1) antibody was selected as a complementary, transient, systemic immune monotherapy. Islets were PEGylated via an optimized protocol, with resulting islets exhibiting robust cell viability and function. Following transplantation, a significant subset of diabetic animals receiving PEGylated islets (60%) or anti-LFA-1 antibody (50%) exhibited long-term (> 100 d) normoglycemia. The combinatorial approach proved synergistic, with 78% of the grafts exhibiting euglycemia longterm. Additional studies examining graft cellular infiltrates at early time points characterized the local impact of the transplant protocol on graft survival. Results illustrate the capacity of a simple polymer grafting approach to impart significant immunoprotective effects via modulation of the local transplant environment, while short-term immunotherapy serves to complement this effect.

Transplantation of PEGylated islets enhances therapeutic efficacy in a diabetic nonhuman primate model

“…NHP islets were surface modified with linear PEG chains using a protocol optimized and validated in rodent islets . Uniform conjugation of PEG to the islet periphery was observed (Figure A) with no visually distinct differences in morphology or viability when compared to untreated control islets (Figure C‐F).…”

“…Transplant studies were initiated to determine if the protective effect of islet PEGylation observed in rodent studies would translate to the NHP. Immunosuppression consisted of induction with thymoglobulin and maintenance with tacrolimus for the first month, followed by a transition to rapamycin monotherapy 28 days after transplant (see Figure top schematic).…”

“…All culture media was sourced from Mediatech. NHS‐PEG‐CH 3 was fabricated, as detailed in Appendix S1 …”

“…Major histocompatibility complex (MHC)‐typed donor and recipient SPF Mauritian cynomolgus monkeys were obtained from the Mannheimer Foundation (Homestead, FL) or Charles River Laboratories (Houston, TX), see Tables S1 and S2, and Data S1. Islets were isolated (day 0), PEGylated (day 1), and characterized and/or transplanted (day 2), as fully described in Appendix S1 …”

Bio-synthetic materials for immunomodulation of islet transplants

“…Similarly, a PEGylated silicon nanopore membrane to encapsulate islets protects islets from cytokine induced inflammation and destruction in vitro (65). Recently, PEGylation alone provided modest immunosuppression in an allogeneic transplant model (66). Combined with regular delivery of immunosuppressive drugs, mice that received PEGylated islets exhibited long-term normoglycemia.…”