Novel minimally invasive assessment of gastrointestinal inflammation in food alle

食物链中胃肠道炎症的新型微创评估

• 批准号: 7540222
• 负责人: Steven Jules Ackerman
• 金额: $ 24.68万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-16 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7540222
• 关键词: Accounting; Address; Adrenal Cortex Hormones; Adult; Affinity; Aftercare; Allergic; Basophils; Biological Assay; Biological Markers; Biopsy; Caring; Cells; Child; Childhood; Chronic; Clinical; Clinical Data; Clinical assessments; Costs and Benefits; Cytoplasmic Granules; DNA Microarray Chip; DNA Microarray format; Data; Deglutition Disorders; Detection; Diagnosis; Diagnostic; Dietary Intervention; Disease; Disease Management; Disease Progression; Disease remission; Endoscopy; Enzyme-Linked Immunosorbent Assay; Eosinophil Granule Proteins; Eosinophilia; Eosinophilic Esophagitis; Epithelial; Esophageal; Esophageal Tissue; Esophageal mucous membrane; Etiology; Expressed Sequence Tags; Feces; Fibrosis; Food; Food Hypersensitivity; Gastroesophageal reflux disease; Gastrointestinal Diseases; Genes; Giardia; Hypersensitivity; IL8 gene; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Intervention; Intestines; Invasive; Length; Life; Measurement; Measures; Mediating; Mediator of activation protein; Messenger RNA; Methods; Monitor; Mucositis; Numbers; Nutritional; Pathogenesis; Pathway interactions; Patient Care; Patients; Peptic Esophagitis; Plasma; Population; Procedures; Proteins; Public Health; Purpose; Quality of life; Research Personnel; Risk; Role; Sampling; Serological; Skin; Specificity; Standards of Weights and Measures; Technology; Testing; Therapeutic; Time; Tissues; Treatment Effectiveness; Tryptase; United States; Western Blotting; base; case control; chemokine; cytokine; diagnosis evaluation; eosinophil; food allergen; gastrointestinal; human CCL26 protein; improved; in vivo; mast cell; novel; prospective; receptor; response; tool; translational study; treatment effect

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.

描述（由申请方提供）：嗜酸性食管炎（EE）是一种日益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中慢性嗜酸性粒细胞炎症的长期后果包括食管重塑，上皮下纤维化，食管狭窄和狭窄，因此强调了这种疾病的重要性。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）反应在启动食管炎性级联反应中的作用仍然不确定，因为单独的RAST测试显示出识别冒犯性食物过敏原的特异性较差，而SPT仍然是识别相关食物过敏原的最佳可用测试。EE的标准治疗包括初始内镜检查和活检，以获得食管组织，以确定嗜酸性粒细胞数量，≥ 15/hpf为诊断性。迄今为止，没有血清学或粪便分析提供与疾病进展与缓解的组织学证据相关的持久结果。反复内镜检查和活检的作用正在争论中，因为成本效益比是未知的，并带来风险。我们假设并提出了初步结果，即Enterotest（TM），一种首先用于检测肠道贾第虫的基于弦的测试，可用于在蛋白质和mRNA水平上评估食管炎症（称为食管弦测试或EST）。该项目的目标是：（1）测试EST作为一种新型、微创、廉价、敏感和特异性方法的有效性，用于测量EE患者的食管炎症，特别是组织嗜酸性粒细胞增多、细胞因子和趋化因子谱以及CD 23、FceRI和类胰蛋白酶水平，以及（2）使用EST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）使用EST检测的管腔炎症介质与EE患者食管活检确定的粘膜炎症相关，（2）EST可用作疾病管理中食管炎症的微创临床评估。目的1将使用EST表征EE患者食管腔微环境中的炎症反应，测量特异性嗜酸性粒细胞表达的炎症介质（嗜酸性粒细胞颗粒蛋白），以确定其与EE疾病的组织病理学特征的相关性。目的2将确定治疗对EE患者食管炎症反应的影响，比较血浆、食管粘膜（活检）和管腔（EST）CD 23、FceRI、类胰蛋白酶、Th 1和Th 2细胞因子、嗜酸性粒细胞活化趋化因子-3和嗜酸性粒细胞颗粒蛋白生物标志物的定量测量，以将变化与治疗诱导的反应相关联。这些研究将开始验证EST作为监测EE食管炎症的微创诊断工具、CD 23/FceRI/IgE的参与以及使用EST代替重复内镜检查和活检确定治疗的组织病理学反应的有效性。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）目前折磨着估计4-6%的美国人口。食管过敏患者的护理是有限的，因为需要初始和重复的内窥镜检查和活检诊断和评估治疗的有效性方面的疾病缓解或进展。本申请的重点是研究验证一种新方法，食管弦测试，通过使用微创现有技术，肠试验（TM）分析食管炎症，并使用这种新的测试，以评估治疗对食管炎症的影响和IgE介导的途径参与嗜酸性粒细胞性食管炎的发病机制。这些研究的结果将通过限制治疗所需的侵入性内镜检查和活检程序的数量，以及通过增加对嗜酸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，改善食物过敏和嗜酸性食管炎患者的生活质量。