UBC Theses and Dissertations

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UBC Theses and Dissertations

The role of Toll-like receptors in islet allograft rejection and normal beta-cell function Hutton, Meredith Julia Hamilton


Diabetes mellitus is both a metabolic and inflammatory syndrome, characterized by hyperglycemia in the presence of insufficient beta-cell mass and high levels of circulating proinflammatory cytokines. Determining the mechanism behind this chronic inflammation is important for developing therapeutic targets, as controlling inflammation may prevent the progression of diabetes, development of secondary disease, and failure of islet allografts. Toll-like receptors (TLRs), a family of pattern recognition receptors of the innate immune system, are important for regulating adaptive immunity. The aim of this project was to determine the role of Toll-like receptor signalling in islet transplantation and normal beta-cell function. The role of TLR signalling in islet transplantation was assessed using a full major histocompatability complex mismatch murine islet allograft model. TLRs are capable of sensing both exogenous and endogenous ligands. Excessive TLR activation during transplantation may promote allograft rejection. To test this hypothesis, islets from TLR-deficient mice were transplanted into chemically-induced diabetic recipients, and graft survival was assessed by monitoring blood glucose levels. Islet grafts deficient for TLR4, or for TLR signalling molecules TRIF and MyD88, had similar graft failure rates to islet grafts from wild-type controls, indicating that islet allograft rejection occurs independently of donor TLR signalling in mice. To determine whether lack of TLR signalling via TRIF and MyD88 affects normal beta-cell function, mice deficient for TRIF or MyD88 were assessed for glucose tolerance, insulin sensitivity and in vitro glucose-stimulated insulin secretion. As TLR-induced inflammation has been demonstrated to enhance insulin resistance and diabetes-associated inflammation, lack of TLR signalling under non-pathological conditions may enhance beta-cell function. Interestingly, mice lacking TRIF demonstrated impaired glucose tolerance, hyperglycemia, hyperinsulinemia and impaired glucose-stimulated insulin secretion. Mice lacking MyD88 had similar glucose tolerance and insulin sensitivity to littermate controls, but displayed a mild impairment in glucose-stimulated insulin secretion. The results of this thesis demonstrate that while TLR signalling is not likely to be essential for islet allograft rejection, TLR signalling may contribute to normal beta-cell function. These findings point to a previously unrecognized role for TLR signalling in glucose homeostasis.

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