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: 7545857
• 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
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7545857
• 关键词: Address; Affect; Alleles; 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; 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; Pathology; Patients; Peptides; Phenotype; Play; Population; Predisposition; Prevention; Principal Investigator; Process; Production; Research Personnel; Role; Serological; Site; Sjogren' 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; high risk; mouse model; novel; oral tolerance; prevent; programs; receptor; research study; response; symposium; tool; treatment strategy

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，由麸质的消耗引发， 遗传易感个体易患乳糜泻的个体表达DQ 2或DQ 3。 DQ 8 HLA II类抗原。诊断是通过肠活检显示绒毛萎缩， 从饮食中去除麸质后就消失了。因为所有患者都是DQ 2或DQ 8， 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CD 4 + T细胞。然而，只有2%的 高加索人群中的DQ 2和DQ 8个体发生乳糜泻，表明 此外，DQ单倍型也参与疾病的发展。更好地 了解HLA II类分子如何影响乳糜泻的发展，我们有 提出了在缺乏小鼠免疫原性的情况下产生表达DQ 2和/或DQ 8的HLA转基因小鼠， II类表达。初步证据表明，DQ 8分子赋予面筋 DQ 8小鼠中的敏感性而非肠病。谷蛋白敏感性的研究进展 肠病可以通过引入自身免疫易感NOD背景而诱导。的 所得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， 疾病根据这些初步数据，提出了以下目标。1.为了检验这一假设 特定的HLA-II类分子导致了麸质敏感性。2.我们将检验这个假设 虽然II类分子对麸质敏感性很重要，但其他易患 自身免疫是发生肠病所必需的。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 很大的潜力，阐明遗传和环境的组成部分， 乳糜泻免疫发病机制和潜在的新的预防或治疗试验 战略布局

项目成果

Novel role of the serine protease inhibitor elafin in gluten-related disorders.

• DOI: 10.1038/ajg.2014.48
• 发表时间: 2014-05
• 期刊: AMERICAN JOURNAL OF GASTROENTEROLOGY
• 影响因子: 9.8
• 作者: Galipeau, Heather J.;Wiepjes, Michelle;Motta, Jean-Paul;Schulz, Jessica D.;Jury, Jennifer;Natividad, Jane M.;Pinto-Sanchez, Ines;Sinclair, Daniel;Rousset, Perrine;Martin-Rosique, Rebeca;Bermudez-Humaran, Luis;Leroux, Jean Christophe;Murray, Joseph A.;Smecuol, Edgardo;Bai, Julio C.;Vergnolle, Nathalie;Langella, Philippe;Verdu, Elena F.
• 通讯作者: Verdu, Elena F.

Gliadin-dependent neuromuscular and epithelial secretory responses in gluten-sensitive HLA-DQ8 transgenic mice.

麸质敏感 HLA-DQ8 转基因小鼠中麦醇溶蛋白依赖性神经肌肉和上皮分泌反应。

• DOI: 10.1152/ajpgi.00225.2007
• 发表时间: 2008
• 期刊: American journal of physiology. Gastrointestinal and liver physiology
• 作者: Verdu,EF;Huang,X;Natividad,J;Lu,J;Blennerhassett,PA;David,CS;McKay,DM;Murray,JA
• 通讯作者: Murray,JA

Sensitization to gliadin induces moderate enteropathy and insulitis in nonobese diabetic-DQ8 mice.

• DOI: 10.4049/jimmunol.1100854
• 发表时间: 2011-10-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Galipeau HJ;Rulli NE;Jury J;Huang X;Araya R;Murray JA;David CS;Chirdo FG;McCoy KD;Verdu EF
• 通讯作者: Verdu EF

Host responses to intestinal microbial antigens in gluten-sensitive mice.

• DOI: 10.1371/journal.pone.0006472
• 发表时间: 2009-07-31
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Natividad JM;Huang X;Slack E;Jury J;Sanz Y;David C;Denou E;Yang P;Murray J;McCoy KD;Verdú EF
• 通讯作者: Verdú EF

Low incidence of spontaneous type 1 diabetes in non-obese diabetic mice raised on gluten-free diets is associated with changes in the intestinal microbiome.

• DOI: 10.1371/journal.pone.0078687
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Marietta EV;Gomez AM;Yeoman C;Tilahun AY;Clark CR;Luckey DH;Murray JA;White BA;Kudva YC;Rajagopalan G
• 通讯作者: Rajagopalan G