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A HLA Mouse Model for Gluten Sensitivity and Enteropathy

麸质敏感性和肠病的 HLA 小鼠模型

基本信息

批准号：
7331471
负责人：
Joseph A Murray
金额：
$ 28.17万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
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/7331471
关键词：
Address Affect Alleles Animal Cancer Model Animal Model Antibody Formation Antigens Autoimmune Diseases Autoimmune Process Autoimmunity B-Lymphocytes Biological Assay Biopsy Bulla CD4 Positive T Lymphocytes Caucasians Caucasoid Race Celiac Disease Cell Line Cells Chemicals Chronic Chronic Disease Class Clinical Colitis Consumption Data Dermatitis Herpetiformis Development Diagnosis Diet Disease Eating Environment Epitopes Excision Genetic Gliadin Glutamic Acid Glutamine Gluten Haplotypes Histocompatibility Antigens Class II Human IL2RA gene Immune response Inbred NOD Mice Individual Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Inflammatory disease of the intestine Insulin-Dependent Diabetes Mellitus Interleukin-10 Intestines Knowledge Lead Ligands Modeling Monitor Mucous Membrane Mus Non obese Numbers Pathology Patients Peptides Phenotype Play Population Predisposition Prevention Principal Investigator Process Production Research Personnel Risk Role Serological Site Sjogren&apos s Syndrome Small Intestines Susceptibility Gene T-Lymphocyte Testing Text Thyroiditis Time Tissues Transgenic Mice Transgenic Organisms Transglutaminases Villous Atrophy Visual Weaning autoimmune gastritis base cytokine design diabetic feeding human study mouse model novel oral tolerance prevent programs receptor research study response symposium tool

项目摘要

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.

乳糜泻是一种慢性炎症性疾病，由食用麸质引发遗传易感人群。易患乳糜泻的个体表达 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就会消失。因为所有患者都是 DQ2 或 DQ8，所以分子在疾病发展中至关重要。最近的研究表明，这些分子将麦醇溶蛋白肽呈递给炎症性肠道 CD4+ T 细胞。然而，只有 2% 高加索人群中的 DQ2 和 DQ8 个体患有乳糜泻，表明 DQ 单倍型之外的因素也参与疾病的发展。为了更好了解 HLA II 类分子如何影响乳糜泻的发展，我们有提议在没有小鼠的情况下产生表达 DQ2 和/或 DQ8 的 HLA 转基因小鼠 II 类表达。初步证据表明 DQ8 分子赋予麸质 B10.DQ8 小鼠具有敏感性，但没有肠病。麸质敏感症的发展自身免疫性 NOD 背景的引入可诱发肠病。这由此产生的 NOD.DQ8 小鼠一旦对麸质敏感，就会出现类似于乳糜泻的肠病疾病。根据这些初步数据，提出以下目标。 1. 检验假设特定的 HLA II 类分子有助于麸质敏感性。 2. 我们将检验假设虽然 II 类分子对于麸质敏感性很重要，但其他易导致麸质敏感性的基因自身免疫是发生肠病所必需的。 3. 为了确定 BIO DQ8 小鼠的原因，虽然对麸质敏感，但不会发展为肠病。这些新颖动物模型的使用阐明基因和环境因素的巨大潜力乳糜泻的免疫发病机制以及可能测试新的预防或治疗方法策略。