A HLA Mouse Model for Gluten Sensitivity and Enteropathy

描述(申请人提供)：乳糜泻是一种慢性炎症性疾病，由基因易感个体摄入面筋引起。易患乳糜泻的个体表达DQ2或DQ8人类白细胞抗原II类抗原。诊断是通过肠道活检显示绒毛萎缩，这种萎缩在从饮食中去除面筋后消失。因为所有患者都是DQ2或DQ8，所以这些分子对疾病的发展至关重要。最近的研究表明，这些分子向炎症性肠道CD4+T细胞递送醇溶蛋白多肽。然而，在高加索人群中，只有2%的DQ2和DQ8个体会发生乳糜泻，这表明除了DQ单倍型外，还有其他因素参与了疾病的发生。为了更好地了解HLAII类分子如何影响乳糜泻的发生发展，我们建议在不表达HLAII类分子的情况下产生表达DQ2和/或DQ8的转基因小鼠。初步证据表明，DQ8分子使B10.DQ8小鼠对面筋敏感，但不会引起肠病。面筋敏感型肠病的发生可能与自身免疫性结节背景的引入有关。由此产生的NOD.DQ8小鼠一旦对面筋致敏，就会患上类似于乳糜泻的肠病。基于这一初步数据，提出了以下目标。1.验证特定的人类白细胞抗原II类分子对面筋敏感的假设。2.我们将检验这一假设，即虽然II类分子对面筋敏感性很重要，但其他易于产生自身免疫的基因也是发生肠病所必需的。3.确定BIO DQ8小鼠虽然对面筋敏感，但没有发生肠病的原因。这些新的动物模型的使用具有很大的潜力来阐明乳糜泻的发病和免疫发病机制的遗传和环境成分，并有可能测试新的预防或治疗策略。

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.