Role of IL-15 in the Pathogenesis of Eosinophilic Esophagitis (EE)

IL-15 在嗜酸性食管炎 (EE) 发病机制中的作用

• 批准号: 8836940
• 负责人: ANIL MISHRA
• 金额: $ 37.63万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 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 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8836940
• 关键词: Adolescent; Adult; Allergens; Allergic; American; Antigen-Presenting Cells; Attention; B-Lymphocytes; Biological; Biological Markers; Biopsy; Biopsy Specimen; Blood; CD8B1 gene; Cell Proliferation; Cell surface; Cells; Childhood; Chronic; Communities; Correlation Studies; Data; Deglutition; Deglutition Disorders; Development; Diagnosis; Diagnostic; Disease; Doxycycline; Eosinophilia; Eosinophilic Esophagitis; Epidemic; Esophageal; Esophageal Diseases; Esophageal Stenosis; Esophagus; Etiology; Experimental Models; Fibrosis; Food; Funding; Gastroesophageal reflux disease; Goals; Grant; Growth; Health; Human; IL4 gene; IgE; Immune response; Immunoglobulin Class Switching; Immunoglobulin G; Individual; Infant Food; Inflammatory; Interleukin-13; Interleukin-15; Interleukin-5; Knockout Mice; Mediating; Mediator of activation protein; Medical; Messenger RNA; Monoclonal Antibodies; Mus; Pain; Pathogenesis; Pathway interactions; Patients; Phenotype; Prevalence; Progress Reports; Proteins; Recovery; Regulation; Reporting; Role; Series; Specificity; Surface; T-Lymphocyte; Testing; Transcript; Transgenic Mice; United States National Institutes of Health; airborne allergen; anti-IgE; base; cell growth; chemokine; cytokine; design; eosinophil; food allergen; global health; human CCL26 protein; innovation; interleukin-15 receptor; mast cell; mastocytosis; novel; novel diagnostics; overexpression; receptor; research study; response; therapeutic target; treatment strategy

DESCRIPTION (provided by applicant): This is a renewal application of two years of the R01 grant funded by NIH American Recovery Reinvestment Act (ARRA). This grant had been funded from July 15, 2009 to June 30, 2011 and has led to a series of fundamental principles concerning the role of Interleukin 15 (IL-15) in EE pathogenesis. This renewal application seeks to extend our basic and translational analysis of EE, aimed at providing the role of IL-15 and IL-15 responsive cells in the regulation of esophageal eosinophilia in human EE. In the first cycle of the two- year R01 grant funding, we identified several key molecules that are responsible for the initiation and progression of EE pathogenesis in experimental models and have developed evidence that these findings apply to human EE. The details of our findings are presented in the progress report. In brief, we have demonstrated that induced mRNA/protein of IL-15 and iNKT cells in the esophageal biopsies of humans EE and provided evidence that IL-15 and iNKT cells have a critical role in the initiation and progression of aeroallergen or food allergen (peanut)-induced experimental EE. IL-15 has been identified as an important player in allergic immune responses; it mediates diverse biological responses, ranging from proliferation and differentiation. Antigen presenting cell-derived IL15 stimulates the proliferation of naive and CD8+ T cells, iNKT cells and enhances the differentiation of naive T cells towards a Th2 phenotype in the presence of IL4. Additionally, we present preliminary data that it activates B cells and induces IgE. Therefore, in the extended cycle of grant tenure, we propose to test the central hypothesis that chronic IL-15 expression leads to the development of IgE-associated EE pathogenesis and that the surface molecules of IL-15, IL-15-responsive cells, chemokines, and mediators are the potential diagnostic and therapeutic target molecules for human EE. The three specific aims will test our central hypothesis. In the first aim, we will test several sub-hypotheses by examining esophageal transcript profile of IL-15 overexpressed mice, role of IL-15 in the induction of mast cells and B cell growth, activation, and proliferation and the mechanism of Ig class switching in EE. A correlation of IL-15 will also be examined for the development of esophageal furrows, rings, and stricture in human EE. The second aim will test the hypothesis that IL-15 and the cell surface molecules and chemokines of IL-15-responsive cells may be novel diagnostic biomarkers for human EE. We will test several related sub-hypotheses concerning the mRNA and protein levels of IL-15, IL-15R¿, IgE, CD1d, V¿24, and chemokines CXCL16 in the blood of normal individuals, gastroesophageal reflux disease (GERD) and EE patients. In the third aim, we propose a set of experiments designed to test several related primary hypotheses focused around iNKT cells and IL-15 being novel target molecules for EE therapy. Our studies are timely given the recent attention that EE is receiving in the medical community.

描述（由应用程序提供）：这是由NIH American Recovervestment Act（ARRA）资助的R01赠款两年的续签应用。该赠款从2009年7月15日至2011年6月30日获得资金，并导致了一系列有关白介素15（IL-15）在EE发病机理中的作用的基本原则。该更新应用旨在扩展我们对EE的基本和翻译分析，旨在提供IL-15和IL-15响应细胞在人EE中食管食管嗜酸性粒细胞调节中的作用。在为期两年的R01赠款资金的第一个周期中，我们确定了几个关键分子，这些分子负责实验模型中EE发病机理的主动性和进展，并开发了这些发现适用于人EE的证据。我们的发现的详细信息在进度报告中介绍。简而言之，我们已经证明了人类食管活检中IL-15和INKT细胞的mRNA/蛋白质诱导的mRNA/蛋白质，并提供了证据，证明IL-15和Inkt细胞在气溶剂或食物过敏原（Peanut）诱导的实验EE中具有至关重要的作用和进展。 IL-15已被确定为过敏免疫反应中的重要参与者。它介导了潜水员的生物反应，范围从增殖和分化。呈现细胞衍生的IL15的抗原刺激了幼稚和CD8+ T细胞，inkt细胞的增殖，并在IL4存在下增强了幼稚T细胞向Th2表型的分化。此外，我们提出了它激活B细胞并诱导IgE的初步数据。因此，在扩大授予任期的延长周期中，我们提议检验中心假设，即慢性IL-15表达会导致IgE相关的EE发病机理的发展，并且IL-15，IL-15反应性细胞，趋化因子和介体的表面分子是对男性遗传分解的潜在诊断诊断和治疗靶标。这三个特定目标将检验我们的中心假设。在第一个目标中，我们将通过检查IL-15过表达的小鼠的食管转录物谱，IL-15在肥大细胞诱导和B细胞生长，激活和增殖中的作用以及EE中IG类转换的机制来测试几个亚烟。还将检查IL-15的相关性，以开发人EE中的食管沟，环和狭窄。第二个目的将检验以下假设：IL-15和IL-15反应性细胞的细胞表面分子和趋化因子可能是人EE的新型诊断生物标志物。我们将测试有关IL-15，IL-15R¿的mRNA和蛋白质水平的几个相关亚螺栓，IL-15R，IgE，CD1D，V¿24和趋化因子CXCL16在正常个体的血液中，胃食管反道疾病（GERD）和EE患者。在第三个目标中，我们提出了一组实验，旨在测试围绕Inkt细胞周围的几种相关主要假设，而IL-15是EE治疗的新型靶标分子。鉴于最近在医学界受到EE的关注，我们的研究是及时的。