Innate and adaptive immunity in celiac disease

乳糜泻的先天性和适应性免疫

基本信息

批准号：
8322027
负责人：
BANA JABRI
金额：
$ 31.6万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-09 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8322027
关键词：
Adoptive Transfer Affect Affinity Alternative Therapies Animal Model Antibodies Antigens Atrophic Binding Biological Assay Bromodeoxyuridine CD4 Positive T Lymphocytes CD94 Antigen Celiac Disease Cell Death Chronic Clinical Complex Cytoplasmic Granules Data Defect Development Diet Disease Down-Regulation Epithelial Cells Epithelium Excision Failure Family member Future Generations Gluten Goals Granzyme HLA-DQ8 antigen High Prevalence Histology Human Iceberg Immune Immune response Immune system Immunoglobulin A Immunoglobulin G In Vitro Individual Inflammatory Inflammatory Bowel Diseases Interleukin-12 Interleukin-15 Interleukin-2 Intestines KLRD1 gene Lamina Propria Ligands Link Longitudinal Studies Lymphocyte MAPK9 gene MHC Class I Genes Mesentery Modeling Mus Natural Immunity Oral Pathogenesis Patients Peptides Phenotype Physiologic pulse Population Publishing Qa-1 Antigen Recombinants Regulatory T-Lymphocyte Relative (related person)Reporter Role Signal Transduction Site Staging System T cell response T-Lymphocyte TNF gene Testing Time Tissues Transgenic Organisms Transglutaminases Up-Regulation Villous Atrophy adaptive immunity base cohort congenic cytotoxic feeding follow-up in vivo insight intestinal epithelium intraepithelial lymph nodes mouse model neutralizing antibody novel oral tolerance overexpression prevent promoter public health relevance receptor receptor expression research study response transglutaminase 2 uptake villin

项目摘要

DESCRIPTION (provided by applicant): Celiac disease is a complex intestinal inflammatory disorder with villous atrophy induced by dietary gluten in HLA-DQ2 or HLA-DQ8 individuals. The disease is the 'tip of an iceberg' including a larger subclinical population with various aspects of dysregulation in response to gluten. Immunological abnormalities associated with gluten uptake include (1) chronic upregulation of IL-15 in the epithelium and lamina propria, (2) massive expansion of natural killer-like intraepithelial cytotoxic lymphocytes (IE-CTL), (3) DQ2 or DQ8-restricted anti- gluten CD4 T cells secreting IFNg? in the lamina propria and (4) signature antibodies against gluten and the tissue transglutaminase (TTG) that binds and deamidates gluten. Villous atrophy may depend on the anti- gluten IFNg?+ CD4 T cell response, the expansion of IE-CTL and the overexpression of IL-15, but the precise links between these effector mechanisms remain unclear. The overarching aim of this proposal will be to model and investigate in vivo the consequences of chronic IL-15 expression using established transgenic systems expressing IL-15 at levels comparable to those observed in disease, and dissecting expression in the intestinal epithelium (villin promoter, V-IL15tg) and outside the epithelium in the lamina propria DC (minimal MHC class I Dd promoter, Dd-IL15tg). The conclusions will then be tested against a cohort of relatives of celiac patients where these immunological abnormalities naturally segregate. The ultimate goal is to combine DQ8 and IL-15 to model the histopathological stages of celiac disease. Specific aim 1, will analyze the impact of IL-15 on the breakdown of oral tolerance to ingested gluten; Specific Aim 2 will analyze the role of IL-15 in the acquisition of a natural killer phenotype by intraepithelial lymphocytes and the development of villous atrophy; and Specific Aim 3, will analyze in human studies the link between IL-15, anti-gluten adaptive immunity and natural killer transformation of intraepithelial lymphocytes. Collectively, these studies will not only provide new insights into the pathogenesis of celiac disease and the major impact of dysregulated IL-15 expression but also, importantly, will guide and refine new generation animal models. Because a strict lifelong gluten-free diet imposes tremendous constraints on patients, such models are long overdue to test alternative therapies that will be developed in the near future. PUBLIC HEALTH RELEVANCE: Celiac Disease is an intestinal inflammatory intestinal disorder with a high prevalence (>1%), that is induced by dietary gluten. Understanding how different components of the immune system contribute to disease and developing a mouse model of celiac disease will have a major impact on our understanding of the disease, and the treatment and follow-up of celiac disease patients.

描述（由申请人提供）：乳糜泻是一种复杂的肠道炎症性疾病，在 HLA-DQ2 或 HLA-DQ8 个体中由膳食麸质诱导绒毛萎缩。这种疾病只是“冰山一角”，包括更大的亚临床人群，这些人群对麸质反应存在各个方面的失调。与麸质摄取相关的免疫异常包括 (1) 上皮和固有层中 IL-15 的慢性上调，(2) 自然杀伤样上皮内细胞毒性淋巴细胞 (IE-CTL) 的大量扩增，(3) DQ2 或 DQ8 限制抗麸质 CD4 T 细胞分泌 IFNg？固有层中的抗体和 (4) 抗麸质的特征抗体以及结合麸质并使麸质脱酰胺的组织转谷氨酰胺酶 (TTG)。绒毛萎缩可能依赖于抗谷蛋白IFNg?+ CD4 T细胞反应、IE-CTL的扩增和IL-15的过度表达，但这些效应机制之间的精确联系仍不清楚。该提案的首要目标是使用已建立的转基因系统来模拟和研究慢性 IL-15 表达的后果，该转基因系统以与疾病中观察到的水平相当的水平表达 IL-15，并剖析肠上皮中的表达（绒毛启动子、 V-IL15tg) 和固有层 DC 上皮外 (最小 MHC I 类 Dd 启动子，Dd-IL15tg)。然后将针对一组乳糜泻患者的亲属对结论进行测试，这些免疫异常在这些患者中自然分离。最终目标是将 DQ8 和 IL-15 结合起来模拟乳糜泻的组织病理学阶段。具体目标1，将分析IL-15对摄入麸质口服耐受性崩溃的影响；具体目标 2 将分析 IL-15 在上皮内淋巴细胞获得自然杀伤表型和绒毛萎缩发展中的作用；具体目标 3 将在人体研究中分析 IL-15、抗麸质适应性免疫和上皮内淋巴细胞自然杀伤转化之间的联系。总的来说，这些研究不仅将为乳糜泻的发病机制和 IL-15 表达失调的主要影响提供新的见解，而且重要的是，还将指导和完善新一代动物模型。由于严格的终身无麸质饮食给患者带来了巨大的限制，因此这种模型早就应该测试将在不久的将来开发的替代疗法。公共卫生相关性：乳糜泻是一种肠道炎症性肠道疾病，发病率很高 (>1%)，由膳食麸质引起。了解免疫系统的不同组成部分如何导致疾病并开发乳糜泻小鼠模型将对我们对该疾病的理解以及乳糜泻患者的治疗和随访产生重大影响。