Mechanistic Analysis of Eosinophilic Esophagitis

嗜酸性粒细胞性食管炎的发病机制分析

• 批准号: 6865230
• 负责人: ANIL MISHRA
• 金额: $ 24.44万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6865230
• 关键词: Aspergillus; RNase protection assay; antigen antibody reaction; antigen presenting cell; biological transport; cellular immunity; clinical research; eosinophilia; esophagus disorder; fungal antigens; helper T lymphocyte; human subject; hypersensitivity; immune response; immunocytochemistry; immunopathology; inflammation; interleukin 13; laboratory mouse; microarray technology; northern blottings; therapy design /development

DESCRIPTION (provided by applicant): Eosinophilic esophagitis (EE) is an inflammatory disease of the esophagus that is being increasingly recognized especially during childhood. Notably, 70% of EE cases develop along with allergic asthma. The histological identification of increased eosinophils in the esophagus occurs in numerous clinical disorders such as food allergy, eosinophilic gastroenteritis, inflammatory bowel disease, and gastroesophageal reflux (GER). Primary esophageal eosinophilic disorders (i.e. EE) are distinguished from secondary disorders (i.e. GER, drug reactions, infections, esophageal leiomyomatosis) based on several factors. For example, EE (also called idiopathic eosinophilic esophagitis, atopic esophagitis and allergic esophagitis) is characterized by high levels of eosinophils in the esophagus, eosinophilia involving the proximal and distal esophagus, and extensive esophageal histopathological changes (e.g. epithelial hyperplasia). Most patients with primary EE also have a high rate of atopic sensitization to aeroallergens and food antigens. Our goal is to provide the basis for developing novel therapeutic approaches for the treatment of EE. Our recent findings indicate that experimental eosinophilic inflammation occurs in the lungs and esophagus following pulmonary delivery of allergen or IL-13, but not the stomach or intestine, demonstrating an intimate immunological connection between the lung and esophagus. In these experimental systems, it is likely that sensitization occurs by pulmonary exposure since oral or intragastric allergen exposure alone fails to elicit eosinophilia. Collectively, our data has led to the central hypothesis that EE develops as a consequence of a Th2 immune response induced by allergen antigen translocation from the lung to the esophagus. In this grant application, we propose three Aims designed to; i) study the antigen translocation and the role of Th2 cytokines in the induction of EE; ii) study the role of antigen presenting cells and regional lymph nodes in EE induction, and finally, and iii) to explore the mechanism of EE in patients. This proposed study would provide new insight into eosinophil-induced esophageal inflammation, enabling us to develop novel approaches to treating eosinophil-associated esophageal diseases.

描述（由申请人提供）：嗜酸性食管炎（EE）是食管的一种炎症性疾病，尤其是在儿童时期被越来越多地认识到。值得注意的是，有70％的EE病例与过敏性哮喘一起发展。食管中嗜酸性粒细胞增加的组织学鉴定发生在许多临床疾病中，例如食物过敏，嗜酸性粒细胞性胃肠炎，炎症性肠病和胃食管反流（GER）。基于多个因素，原发性食管嗜酸性疾病（即EE）与次要疾病（即GER，药物反应，感染，食管静脉瘤病）区分开来。例如，EE（也称为特发性嗜酸性食管炎，特应食管炎和过敏性食管炎）的特征是食管中的嗜酸性粒细胞高水平，嗜酸性粒细胞，伴有近端和远端食管的嗜酸性粒细胞，以及广泛的食管食管组织病态病态变化（E.g.G.G.G.G.G.G.G.G.G.G.G.G.G.G.G.G.G.Epply epecia）。大多数原发性EE患者对气蚀剂和食品抗原的特应特征性敏感性也很高。我们的目标是为开发EE治疗的新型治疗方法提供基础。我们最近的发现表明，在过敏原或IL-13肺部递送后，肺和食管发生了实验性嗜酸性炎症，但胃或肠道却没有表现出肺和食道之间的亲密免疫联系。在这些实验系统中，由于口腔或胃内过敏原暴露仅会引起嗜酸性粒细胞增多，因此很可能是通过肺部暴露而发生的。总体而言，我们的数据导致了一个中心假设，即EE是由于过敏原抗原易位从肺部到食道引起的Th2免疫反应而发展的。在此赠款应用程序中，我们提出了三个旨在的目标： i）研究抗原易位和Th2细胞因子在EE诱导中的作用； ii）研究抗原呈现细胞和区域淋巴结在EE诱导中的作用，最后以及iii）探索患者EE机理的作用。这项拟议的研究将为嗜酸性粒细胞引起的食管炎症提供新的见解，从而使我们能够开发出新的方法来治疗嗜酸性粒细胞相关的食管疾病。