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

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 (>100d) normoglycemia. The combinatorial approach proved synergistic, with 78% of the grafts exhibiting euglycemia long-term. 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.