A HLA Mouse Model for Gluten Sensitivity and Enteropathy

麸质敏感性和肠病的 HLA 小鼠模型

• 批准号: 7037861
• 负责人: Joseph A Murray
• 金额: $ 29.6万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7037861
• 关键词: T lymphocyte; autoimmunity; celiac disease; dermatitis; disease /disorder model; enzyme linked immunosorbent assay; flow cytometry; gene expression; genetic susceptibility; genetically modified animals; histocompatibility antigens; hypersensitivity; immunogenetics; laboratory mouse; model design /development; pathogenic diet; plant proteins

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.

描述（由申请人提供）：乳糜泻是一种慢性炎症性疾病，由遗传易感个体摄入麸质引发。易患乳糜泻的个体表达DQ 2或DQ 8 HLA II类抗原。诊断是通过肠活检显示绒毛萎缩，这消失后，从饮食中删除面筋。因为所有患者都是DQ 2或DQ 8，所以这些分子在疾病发展中至关重要。最近的研究表明，这些分子将麦胶蛋白肽呈递给炎性肠道CD 4 + T细胞。然而，在高加索人群中，所有DQ 2和DQ 8个体中只有2%发展为乳糜泻，这表明除了DQ单倍型之外的因素也参与了疾病的发展。为了更好地理解HLA II类分子如何影响乳糜泻的发展，我们提出在缺乏小鼠II类表达的情况下产生表达DQ 2和/或DQ 8的HLA转基因小鼠。初步证据表明，DQ 8分子在B10.DQ 8小鼠中赋予麸质敏感性但不赋予肠病。谷蛋白敏感性肠病的发展可以通过引入自身免疫易感性NOD背景来诱导。所得的NOD. DQ 8小鼠一旦对麸质致敏，就会发展出类似于乳糜泻的肠病。根据这些初步数据，提出了以下目标。1.为了验证特定的HLA II类分子有助于面筋敏感性的假设。2.我们将测试的假设，虽然第二类分子是重要的面筋敏感性，其他基因，易患自身免疫性是必要的发展肠病。3.为了确定为什么BIO DQ 8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具有很大的潜力，用于阐明乳糜泻的起始和免疫发病机制的遗传和环境成分，并可能测试新的预防或治疗策略。