Type-1 diabetes (T1D) is an autoimmune disorder characterized by T cell-mediated destruction of pancreatic p-cells. To understand how T cell responses against p cells are provoked is the long-term goal of our work. This proposal is based on the hypothesis that disruptions in the gut epithelium impinge on the initiation of T1D, by exposing dendritic cells (DCs) to enteric factors that boost their capacity to present p cell antigens to potentially diabetogenic T cells. Several findings lead to this hypothesis. First, intestinal permeability and inflammation are exaggerated in diabetes-prone rats before insulitis onset and in patients with T1D. Second, intestinal abnormalities such as hypertrophy or hyperplasia of intestinal villi have been observed in pre- insulitic, diabetes-prone rats. Third, there is a very high prevalence among T1D patients of gluten-induced intestinal inflammation, or celiac disease, and NOD mice exhibit pathogenic hallmarks of celiac disease. Fourth, gluten exhibits diabetogenic potential in genetically susceptible subjects. Finally, our recent studies indicate that perturbations of the gut epithelium modify the course of T1D. Despite an abundance of clinical and epidemiological studies implicating intestinal barrier dysfunction in T1D, the mechanistic underpinnings of this association remain elusive. The objective of this proposal is to elucidate the cellular and molecular mechanisms by which intestinal barrier function regulates the pancreatic autoimmune response.
The specific aims are to: 1} Determine whether alterations to the intestinal epithelium affect both MHC class I- and class ll-restricted T cell responses to p cell Ags. These experiments will ascertain the impact of altered intestinal barrier function on the proliferation, activation, survival and effector functions of p cell- specific, CD4+ and CD8+ T cells;2) Define how changes in intestinal barrier function impact DC function in pancLNs. Here we will determine the impact of mild injury to the intestinal epithelium on the differentiation, maturation, and Ag presentation capacity of specific DC subsets of pancLNs. We will also assess the molecular mechanism by which intestinal injury alters DC function by testing the role of NFicB activation in these processes;3) Evaluate the role of dietary wheat gluten in provoking the anti-p-cell immune response. These experiments will monitor the impact of alimentary gluten proteins on the priming of p-cell-reactive T cells in pancLNs and the maturation of DCs.
The aim of these experiments is to pinpoint the specific mechanism by which gluten provokes pancreatic autoimmunity. The proposed studies will yield insights into the link between environmental provocation and autoimmune pathogenesis.
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