A HLA Mouse Model for Gluten Sensitivity and Enteropathy

描述（由申请人提供）：乳糜泻是一种慢性炎症性疾病，由遗传易感个体食用麸质引发。乳糜泻易感个体表达DQ2或DQ8 HLA II类抗原。诊断是通过肠道活检显示绒毛萎缩，从饮食中去除麸质后消失。因为所有患者要么是DQ2要么是DQ8，这些分子在疾病发展中至关重要。最近的研究表明，这些分子向炎症性肠CD4+ T细胞提供麦胶蛋白肽。然而，在高加索人群中，只有2%的DQ2和DQ8个体发展为乳糜泻，这表明除了DQ单倍型外，其他因素也参与了疾病的发展。为了更好地了解HLA II类分子如何影响乳糜泻的发展，我们提出在小鼠II类表达缺失的情况下，产生表达DQ2和/或DQ8的HLA转基因小鼠。初步证据表明，DQ8分子在B10中引起麸质敏感，而不是肠病。DQ8鼠标。麸质敏感肠病的发展可诱导引入自身免疫性NOD背景。由此产生的点头。DQ8小鼠一旦对麸质敏感，就会出现类似乳糜泻的肠病。基于这些初步数据，提出了以下目标。1. 为了验证特异性HLA II类分子对谷蛋白敏感性的影响。2. 我们将验证这一假设，即虽然II类分子对麸质敏感性很重要，但其他易产生自身免疫的基因对肠病的发生是必要的。3. 确定为什么BIO DQ8小鼠虽然对麸质敏感，但不会发生肠病。这些新型动物模型的使用对于阐明乳糜泻起始和免疫发病机制的遗传和环境因素以及潜在地测试新的预防或治疗策略具有很大的潜力。

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.