Innate and adaptive immunity in celiac disease

乳糜泻的先天性和适应性免疫

• 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
• 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

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-DQ 2或HLA-DQ 8个体中由膳食麸质诱导绒毛萎缩。这种疾病是“冰山一角”，包括一个更大的亚临床人群，在响应面筋的各个方面失调。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）天然的类上皮细胞毒性淋巴细胞（IE-CTL）的大量扩增，（3）DQ 2或DQ 8限制性抗麸质CD 4 T细胞分泌IFNg？ 在固有层中，以及（4）针对谷蛋白的特征抗体和结合谷蛋白并使谷蛋白脱酰胺的组织转氨酶（TTG）。绒毛萎缩可能依赖于抗谷蛋白IFNg？+ CD 4 T细胞应答、IE-CTL的扩增和IL-15的过表达，但这些效应机制之间的确切联系尚不清楚。本提案的首要目标是使用已建立的表达IL-15的转基因系统在体内模拟和研究慢性IL-15表达的后果，所述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，并且解剖肠上皮中的表达（绒毛蛋白启动子，V-IL 15 tg）和固有层DC中的上皮外的表达（最小MHC I类Dd启动子，Dd-IL 15 tg）。然后将针对乳糜泻患者的亲属队列测试这些结论，其中这些免疫异常自然分离。最终目标是将联合收割机DQ 8和IL-15组合以模拟乳糜泻的组织病理学阶段。具体目标1，将分析IL-15对摄入麸质的口服耐受性破坏的影响;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;和特异性目标3，将在人类研究中分析IL-15，抗麸质适应性免疫和上皮内淋巴细胞的自然杀伤转化。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，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对患者施加了巨大的限制，因此这些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：乳糜泻是一种高患病率（>1%）的肠道炎症性疾病，由膳食麸质引起。了解免疫系统的不同组成部分如何促进疾病，并开发腹腔疾病的小鼠模型，将对我们了解该疾病以及腹腔疾病患者的治疗和随访产生重大影响。