Role of IL-15 in the Pathogensis of Eosinophilic Esophagitis

IL-15在嗜酸性食管炎发病中的作用

• 批准号: 7560476
• 负责人: ANIL MISHRA
• 金额: $ 37.18万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7560476
• 关键词: Acids; Address; Adult; Allergens; Allergic; Amino Acids; Anaphylaxis; Applications Grants; Arthritis; Asthma; Attention; Australia; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Basophils; Blood; Brazil; C10; CD4 Positive T Lymphocytes; CD4 gene; CD8B1 gene; Case Series; Cell Lineage; Cells; Chest Pain; Colitis; Communities; Complement component C1s; Data; Deglutition Disorders; Dendritic Cells; Development; Diagnostic; Diet; Disease; England; Eosinophilia; Eosinophilic Esophagitis; Epigastric; Epithelial Cells; Esophageal; Esophageal mucous membrane; Esophagus; Etiology; Experimental Models; Failure to Thrive; Food; Food Hypersensitivity; Gene Expression; Genes; Goals; Growth; Homing; Human; Hypersensitivity; IL15 gene; IgE; Incidence; Individual; Inflammation; Inflammatory; Interleukin Receptor; Interleukin-15; Interleukins; Intervention; Intestines; Italy; Japan; Life; Light; Lymphocyte; Mediating; Medical; Memory; Messenger RNA; Modeling; Molecular; Mus; Pathogenesis; Pathology; Patients; Peptic Esophagitis; Proteins; Recording of previous events; Role; Spain; Switzerland; Symptoms; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic Intervention; Time; Translating; Vomiting; Wild Type Mouse; airborne allergen; base; cell type; chemokine; cytokine; design; eosinophil; feeding; human disease; improved; infancy; innovation; insight; intraepithelial; killer T cell; mast cell; novel; novel therapeutics; overexpression; pre-clinical; public health relevance; response

DESCRIPTION (provided by applicant): Esophageal eosinophilia has a strong association with T helper type 2 (Th2) allergic responses and occurs in a variety of states including eosinophilic esophagitis (EE). Recently, we made a novel observation that local induction of Th2 cytokines, eosinophils and T cells are critical in the pathogenesis of EE. Despite these efforts and findings, we are still unable to target specific cell types, chemokine or cytokine for therapeutic intervention strategy for the treatment of EE. In order to further provide insight into the molecular and cellular mechanisms of EE pathogenesis, we now focus our attention to investigate the role of IL-15 and iNKT cells in EE pathogenesis. The rationale behind understanding their role in EE is, i) IL-15 and iNKT cell associated genes are induced in both experimental and human EE; ii) IL-15 is produced by a number of inflammatory cells including dendritic cells and epithelial cells; iii) IL-15 is required for the development of naove and memory CD8 T cells, intestinal intraepithelial lymphocytes (IEL), NK and iNKT cell lineages; and iv) IL-15 and iNKT cells are implicated in a broad range of autoimmune and allergic diseases but has not previously been studies in EE. In this grant proposal, the PI proposes to test the hypothesis that the pathogenesis of EE involves IL-15-induced iNKT cell-mediated inflammation. We propose three aims designed to test the role of IL-15 in experimental and human EE. In the first aim, we will examine the critical role of IL-15 in the induction of EE. The second aim will be focused on the mechanism of iNKT cell esophageal homing, activation, and the role in EE pathogenesis. In the third aim, we will translate our pre-clinical observations into the human EE by examining the levels of IL-15, iNKT cells and their related homing and activation molecules in normal individuals and EE patients, and analyzing their correlations with the esophageal eosinophilia. Our studies are timely given the recent attention that EE is receiving in the medical community. Eosinophilic esophagitis (EE) is a worldwide growing medical problem; however, the etiology of the disease pathogenesis is not well understood. The goal of our proposed study is to identify a target molecule for EE therapy by examining the role of IL-15 and iNKT cells in the pathogenesis of EE. PUBLIC HEALTH RELEVANCE: Eosinophilic esophagitis (EE) is a worldwide growing medical problem; however, the etiology of the disease pathogenesis is not well understood. The goal of our proposed study is to identify a target molecule for EE therapy by examining the role of IL-15 and iNKT cells in the pathogenesis of EE.

描述（由申请人提供）：食管嗜酸性粒细胞菌与T辅助型2型（TH2）过敏反应有很强的关联，并且发生在包括嗜酸性食管炎（EE）在内的多种状态中。最近，我们对Th2细胞因子，嗜酸性粒细胞和T细胞的局部诱导在EE的发病机理中至关重要。尽管进行了这些努力和发现，但我们仍然无法针对特定的细胞类型，趋化因子或细胞因子来治疗EE治疗策略。为了进一步洞悉EE发病机理的分子和细胞机制，我们现在将注意力集中在研究IL-15和INKT细胞在EE发病机理中的作用。理解其在EE中的作用的基本原理是I）IL-15和Inkt细胞相关的基因在实验和人EE中均被诱导； ii）IL-15是由包括树突状细胞和上皮细胞在内的许多炎性细胞产生的； III）IL-15是发展NAOVE和记忆CD8 T细胞，肠内淋巴细胞（IEL），NK和Inkt细胞谱系所必需的； IV）IL-15和INKT细胞与广泛的自身免疫性和过敏性疾病有关，但以前尚未在EE中进行研究。在这项赠款建议中，PI提出了检验以下假设：EE的发病机理涉及IL-15诱导的INKT细胞介导的炎症。我们提出的三个目标旨在测试IL-15在实验和人EE中的作用。在第一个目标中，我们将研究IL-15在EE诱导中的关键作用。第二个目的将集中在inkt细胞食管归巢，激活和在EE发病机理中的作用的机理。在第三个目标中，我们将通过检查正常个体和EE患者的IL-15，Inkt细胞及其相关的归巢和激活分子的水平，将我们的临床前观察结果转化为人EE，并分析其与食管嗜酸性嗜酸性嗜酸盐的相关性。鉴于最近在医学界受到EE的关注，我们的研究是及时的。嗜酸性食管炎（EE）是全球越来越多的医学问题。但是，疾病发病机理的病因尚不清楚。我们提出的研究的目的是通过检查IL-15和INKT细胞在EE发病机理中的作用来鉴定EE治疗的靶分子。公共卫生相关性：嗜酸性食管炎（EE）是一个在全球培训的医疗问题；但是，疾病发病机理的病因尚不清楚。我们提出的研究的目的是通过检查IL-15和INKT细胞在EE发病机理中的作用来鉴定EE治疗的靶分子。