Mechanistic Analysis of Eosinophilic Esophagitis

嗜酸粒细胞性食管炎的发病机制分析

• 批准号: 7046689
• 负责人: ANIL MISHRA
• 金额: $ 23.86万
• 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/7046689
• 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）：嗜酸粒细胞性食管炎（EE）是一种食管炎症性疾病，尤其是在儿童时期，人们越来越认识到这种疾病。值得注意的是，70% 的 EE 病例伴有过敏性哮喘。食管中嗜酸性粒细胞增多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）。原发性食管嗜酸性粒细胞疾病（即 EE）与继发性疾病（即 GER、药物反应、感染、食管平滑肌瘤病）基于多种因素进行区分。例如，EE（也称为特发性嗜酸性粒细胞性食管炎、特应性食管炎和过敏性食管炎）的特点是食管内嗜酸性粒细胞水平高，嗜酸性粒细胞增多累及近端和远端食管，以及广泛的食管组织病理学改变（例如上皮增生）。大多数原发性 EE 患者对空气过敏原和食物抗原也有很高的特应性过敏率。我们的目标是为开发治疗 EE 的新治疗方法提供基础。我们最近的研究结果表明，在肺部输送过敏原或 IL-13 后，实验性嗜酸性粒细胞炎症发生在肺和食道中，而不是胃或肠，这表明肺和食道之间存在密切的免疫联系。在这些实验系统中，由于单独口服或胃内过敏原暴露无法引起嗜酸性粒细胞增多，因此肺部暴露很可能发生致敏。总的来说，我们的数据得出了一个中心假设，即 EE 的发生是过敏原抗原从肺转移到食道诱导的 Th2 免疫反应的结果。在此拨款申请中，我们提出了三个目标： i) 研究抗原易位和Th2细胞因子在EE诱导中的作用； ii) 研究抗原呈递细胞和区域淋巴结在 EE 诱导中的作用，最后 iii) 探索患者 EE 的机制。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，使我们能够开发出治疗嗜酸性粒细胞相关食管疾病的新方法。