Novel minimally invasive assessment of gastrointestinal inflammation in food alle

描述（由申请人提供）：嗜酸性粒细胞性食管炎（EE）是一种越来越被认识到的胃肠道疾病，约占儿童和成人吞咽困难和食物嵌塞病例的50%。EE慢性嗜酸性粒细胞炎症的长期后果包括食管重塑，伴有上皮下纤维化，食管狭窄和狭窄，因此强调了该疾病的重要性。转化研究表明，90%的EE患者对饮食干预有反应，支持体液（IgE）和/或细胞介导的食物过敏的作用。ige介导的肥大细胞（或嗜碱性粒细胞）反应在启动食管炎症级联反应中的作用仍不确定，因为单独的RAST测试在识别有害食物过敏原方面的特异性较差，而SPTs仍然是识别相关食物过敏原的最佳可用测试。EE的护理标准包括初始内镜检查和食管组织活检，以确定嗜酸性粒细胞的数量，=15/hpf为诊断标准。迄今为止，没有血清学或粪便分析提供与疾病进展和缓解的组织学证据相关的持久发现。由于成本效益比未知且存在风险，反复内镜检查和活检的作用仍在争论中。我们假设并提出初步结果，Enterotest （tm）是一种最初用于检测肠贾第鞭毛虫的基于字符串的测试，可用于评估蛋白质和mRNA水平的食管炎症（称为食管字符串测试或EST）。该项目的目标是：(1)测试EST作为一种新型的、微创的、廉价的、敏感的和特异性的方法来测量EE患者的食管炎症的有效性，特别是组织嗜酸性粒细胞、细胞因子和化因子谱，以及CD23、FceRI和胰蛋白酶的水平；(2)使用EST来监测营养或皮质类固醇治疗后的疾病状态。我们提出了两个综合假设：(1)用EST检测到的腔内炎症介质与EE患者食管活检确定的粘膜炎症相关，(2)EST可作为食管炎症的微创临床评估，用于疾病管理。目的1将使用EST表征EE患者食管腔微环境中的炎症反应，测量特定的嗜酸性粒细胞表达的炎症介质（嗜酸性粒细胞颗粒蛋白），以确定它们与EE疾病的组织病理学特征的关联。目的2将确定治疗对EE患者食管炎症反应的影响，通过定量测量血浆、食管粘膜（活检）和腹腔（EST） CD23、FceRI、胰蛋白酶、Th1和Th2细胞因子、eotaxin-3和嗜酸性粒细胞颗粒蛋白生物标志物，以确定治疗与治疗诱导反应的相关性。这些研究将开始验证EST作为一种微创诊断工具，用于监测EE中食管炎症，CD23/FceRI/IgE的参与，以及使用EST来确定治疗的组织病理反应，而不是重复的内窥镜检查和活检的有效性。食物过敏性疾病（包括嗜酸性粒细胞性胃肠道疾病，如嗜酸性粒细胞性食管炎）目前约占美国人口的4-6%。食管过敏患者的护理是有限的，因为需要进行初始和反复的内窥镜检查和活检来诊断和评估疾病缓解或进展方面的治疗效果。本申请的重点是研究验证一种新的方法，食管弦试验，通过使用微创现有技术Enterotest（tm）来分析食管炎症，并使用这种新的试验来评估治疗对食管炎症的影响以及ige介导的途径在嗜酸性粒细胞性食管炎发病机制中的参与。这些研究的结果将通过限制其护理所需的侵入性内窥镜检查和活检程序的数量，并通过增加对嗜酸性粒细胞性食管炎和其他食物过敏性胃肠道疾病发病机制的全面了解，提高食物过敏和嗜酸性粒细胞性食管炎患者的生活质量。

DESCRIPTION (provided by applicant): Eosinophilic esophagitis (EE) is an increasingly recognized gastrointestinal disease that accounts for ~50% of pediatric and adult cases of dysphagia and food impaction. Long-term consequences of chronic eosinophilic inflammation in EE include esophageal remodeling, with subepithelial fibrosis, and esophageal narrowing and strictures, thus emphasizing the importance of this disease. Translational studies show that >90% of EE patients respond to dietary interventions, supporting a role for humoral (IgE) and/or cell-mediated food allergy. The role of IgE-mediated mast cell (or basophil) responses in initiating the esophageal inflammatory cascade remains uncertain since RAST testing alone shows poor specificity for identifying the offending food allergen(s), whereas SPTs remain the best available test to identify relevant food allergens. Standard of care for EE includes initial endoscopy with biopsy for obtaining esophageal tissue to determine the numbers of eosinophils, =15/hpf being diagnostic. No serological or stool analyses to date provide durable findings that correlate with histological evidence of disease progression vs. remission. The role of repeated endoscopy and biopsy is under debate, since the cost-benefit ratio is unknown and entails risks. We hypothesize and present preliminary results that the Enterotest,(tm) a string-based test first used for detection of intestinal Giardia, can be used to assess esophageal inflammation at the protein and mRNA levels (termed the Esophageal String Test or EST). The project's objectives are to: (1) test the efficacy of the EST as a novel, minimally invasive, inexpensive, sensitive and specific method for measuring esophageal inflammation in EE patients, particularly tissue eosinophilia, cytokine and chemokine profiles, and levels of CD23, FceRI and tryptase, and (2) use the EST to monitor disease status following nutritional or corticosteroid treatments. We propose two integrated hypotheses that: (1) luminal inflammatory mediators detected using EST correlate with mucosal inflammation as determined by esophageal biopsy in patients with EE, and (2) the EST can be used as a minimally invasive clinical assessment of esophageal inflammation for disease management. Aim 1 will characterize the inflammatory response in the esophageal luminal microenvironment of EE patients using the EST, performing measurements of specific eosinophil-expressed inflammatory mediators (eosinophil granule proteins), to determine their associations with the histopathologic features of EE disease. Aim 2 will determine the impact of treatment on the esophageal inflammatory response in EE patients comparing quantitative measurements of plasma, esophageal mucosa (biopsy) and luminal (EST) CD23, FceRI, tryptase, Th1 and Th2 cytokines, eotaxin-3, and eosinophil granule protein biomarkers to correlate changes with treatment-induced responses. These studies will begin to validate the EST as a minimally invasive diagnostic tool for monitoring esophageal inflammation in EE, the participation of CD23/FceRI/IgE, and the efficacy of using the EST to determine histopathologic responses to treatment in lieu of repeated endoscopies and biopsies. (PUBLIC HEALTH RELEVANCE) Food allergic diseases (including eosinophilic gastrointestinal diseases such as eosinophilic esophagitis) currently afflict an estimated 4-6% of the United States population. Care of patients with esophageal allergies is limited because of the need for initial and repeated endoscopies and biopsies for diagnosis and evaluation of the effectiveness of treatment in terms of disease remission or progression. This application focuses on studies validating a novel method, the Esophageal String Test, for analyzing esophageal inflammation through the use of minimally invasive existing technology, the Enterotest(tm), and using this novel test to evaluate the effects of treatment on esophageal inflammation and the participation of IgE-mediated pathways in the pathogenesis of eosinophilic esophagitis. Results from these studies will improve the quality of life for patients with food allergies and eosinophilic esophagitis by limiting the number of invasive endoscopy with biopsy procedures required for their care, and by increasing overall understanding of the pathogenesis of eosinophilic esophagitis and other food allergic gastrointestinal diseases.