Innate and adaptive immunity in celiac disease

乳糜泻的先天性和适应性免疫

• 批准号: 8528559
• 负责人: BANA JABRI
• 金额: $ 30.5万
• 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/8528559
• 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）：腹腔疾病是一种复杂的肠道炎症性疾病，在HLA-DQ2或HLA-DQ8个体中由饮食麸质引起的绒毛萎缩。该疾病是“冰山一角”，包括较大的亚临床人群，响应麸质，具有各个方面。与麸质吸收相关的免疫异常包括（1）（1）在上皮和椎板中慢性上调IL-15，（2）（2）自然杀手型上皮内细胞毒性淋巴细胞（IE-CTL）（IE-CTL）的大量扩张，（IE-CTL），（IE-CTL），（IE-CC2或DQ2或DQ8或DQ8-RESTRIDEN-fILIDENT-GLID-GLIDECTING cD4 tT-4 TT-4？ 在固有椎板和（4）针对面筋的抗体和结合和脱膜面筋的组织转谷氨酰胺酶（TTG）。绒毛萎缩可能取决于抗麸质IFNG？+ CD4 T细胞反应，IE-CTL的扩展和IL-15的过表达，但是这些效应器机制之间的确切联系尚不清楚。 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）。然后，将对这些免疫异常自然隔离的腹腔患者的亲属进行测试。最终目标是结合DQ8和IL-15，以建模乳糜泻的组织病理学阶段。具体目标1将分析IL-15对口服耐受性对摄入面筋的影响的影响；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的发展中的作用；和特定的目标3将在人类研究中分析IL-15，抗浮雕的适应性免疫和上皮内淋巴细胞的自然杀手转化之间的联系。总的来说，这些研究不仅将提供有关乳糜泻的发病机理以及IL-15表达失调的主要影响的新见解，而且重要的是，重要的是指导和完善新一代动物模型。由于严格的无麸质饮食对患者施加了巨大的限制，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，患病率很高（> 1％），是由饮食麸质引起的。了解免疫系统的不同成分如何促进疾病并发展腹腔疾病的小鼠模型将对我们对疾病的理解以及腹腔疾病患者的治疗和随访产生重大影响。