A HLA Mouse Model for Gluten Sensitivity and Enteropathy

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DESCRIPTION (provided by applicant): Celiac disease is a chronic inflammatory disorder that is triggered by the consumption of gluten in genetically susceptible individuals. Individuals susceptible to celiac disease express either DQ2 or the DQ8 HLA class II antigen. Diagnosis is by intestinal biopsy demonstrating villous atrophy, which disappears upon removal of gluten from the diet. Because all patients are either DQ2 or DQ8 these molecules are crucial in disease development. Recent studies have demonstrated that these molecules present gliadin peptides to inflammatory intestinal CD4+ T cells. However, only 2% of all DQ2 and DQ8 individuals in the Caucasian population develop celiac disease, indicating that factors in addition the DQ haplotype are involved in the development of disease. To better understand how HLA class II molecules affect the development of celiac disease, we have proposed to generate HLA transgenic mice expressing DQ2 and /or DQ8 in the absence of mouse class II expression. Preliminary evidence demonstrates that the DQ8 molecule confers gluten sensitivity but not enteropathy in the B10.DQ8 mouse. The development of gluten sensitive enteropathy can be induced with the introduction of the autoimmune prone NOD background. The resultant NOD.DQ8 mouse, once sensitized to gluten, develops enteropathy similar to celiac disease. Based on this preliminary data, the following aims are proposed. 1. To test the hypothesis that specific HLA class II molecules contribute to gluten sensitivity. 2. We will test the hypothesis that while class II molecules are important for gluten sensitivity, other genes that predispose to autoimmunity are necessary to develop enteropathy. 3. To determine why the BIO DQ8 mice, though sensitive to gluten, do not develop enteropathy. The use of these novel animal models has great potential for elucidating the genetic and environmental components of the initiation and immunopathogenesis of celiac disease and potentially testing new prevention or treatment strategies.