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Chemokine-mediated modulation of autoimmunity in type 1 diabetes

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Title: Chemokine-mediated modulation of autoimmunity in type 1 diabetes
Author: Bischoff, Loraine Helena
Degree Doctor of Philosophy - PhD
Program Pathology and Laboratory Medicine
Copyright Date: 2012
Publicly Available in cIRcle 2012-08-30
Abstract: Type 1 diabetes is an autoimmune disorder characterized by destruction of insulin-producing beta cells by autoreactive T cells. Despite management of type 1 diabetes with insulin therapy, affected individuals face devastating complications, such as blindness and kidney failure. Islet transplantation has emerged as a promising therapy to replace beta cells; unfortunately, it is still challenged by a high rate of graft failure due to allo- and recurrent auto-immune responses. The pathogenesis of type 1 diabetes results from a combination of genetic and environmental factors that cause an imbalance in regulatory mechanisms, including defects in T regulatory (Treg) and natural killer T (NKT) cells. We believe that enhancing the activity of these cells locally may have the desirable effect of modulating the immune response against beta cells. Interestingly, the chemokines CCL22 and CCL17 preferentially recruit Tregs. We hypothesized that expression of these chemokines in islets would prevent beta cell destruction by enhancing influx of immunoregulatory cells. We used viral vectors to induce expression of CCL22 or CCL17 in islets and tested this hypothesis in models of spontaneous and recurrent autoimmune diabetes in the non-obese diabetic mouse. We found that CCL22 expression in pancreatic islets prevented diabetes development and protected islet transplants from recurrent autoimmunity, although not indefinitely. CCL22-expressing islets recruited Tregs, invariant NKT and plasmacytoid dendritic cells, resulting in a tolerogenic milieu characterized by lower IFNγ levels and increased expression of indoleamine 2,3-dioxygenase. CCL22 induced expression of CTLA-4, ICOS and CD62L on Tregs and enhanced their ability to modulate dendritic cell function, indicatory of a superior suppressive function. Notably, depletion of Tregs abrogated CCL22’s protective effect, suggesting that CCL22 modulatory properties are dependent on Tregs. When comparing CCL22 and CCL17, we found similar recruitment of Tregs and invariant NKT cells, but unlike CCL22, CCL17 did not impact Treg function. Nevertheless, CCL17 expression in islet grafts was equally protective from recurrent autoimmunity. Our findings suggest a novel strategy for protecting beta cells from immune attack, by using chemokines CCL22 or CCL17 to harness the natural regulatory properties of immune cells such as Tregs and invariant NKT cells.
URI: http://hdl.handle.net/2429/43100
Scholarly Level: Graduate

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