PEGylation and bioactive modification of pancreatic islet surfaces to enhance graft survival in cell therapy for Type I Diabetes

Islet transplantation is a promising therapy for Type 1 Diabetes Mellitus (T1DM), an autoimmune disease characterized by the destruction of the insulin producing beta cells pivotal to regulation of blood glucose. Despite vigorous and often injurious systemic immunosuppression, host inflammatory and immune responses lead to islet dysfunction and destruction over time. PEGylation, the grafting of poly(ethylene glycol) (PEG) to the periphery of cells or cell clusters, has the potential to mitigate inflammation and immune recognition via generation of a steric barrier. While explored as a plausible immunoprotective barrier in previous studies, this dissertation seeks to fully characterize the impact of an optimized PEG grafting procedure on long-term engraftment, as well as explore its potential to boost the efficacy of systemic immunosuppression. The effect of PEGylation on the survival of islet allografts was assessed in both murine and non-human primate (NHP) models of transplantation. Further, the potential of Staudinger ligation for tethering bioactive conjugates to confer immunomodulatory function was screened. The aim of this work was to determine the potential of and mechanism by which PEG protects islet allografts from the host immune response and establish the feasibility of incorporating bioactive motifs onto surfaces to further enhance graft survival.