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Eosinophil functions in allergic gastrointestinal diseases

嗜酸性粒细胞在过敏性胃肠道疾病中的作用

基本信息

批准号：
9900740
负责人：
Lisa Ann Spencer
金额：
$ 38.88万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-11-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9900740
关键词：
Abdominal Pain Adrenal Cortex Hormones Adult Affect Allergens Allergic Anatomy Antigen-Presenting Cells Antigens Automobile Driving CD4 Positive T Lymphocytes Cell physiology Child Clinical Pathology Data Deglutition Disorders Development Diarrhea Disease Disease Management Elemental Diets Failure to Thrive Food Food Aversion Frequencies Functional disorder Gastrointestinal Diseases Gastrointestinal tract structure Goals Home environment Human Humoral Immunities IgE Immune Immune response Immunoglobulin G Immunologics In Vitro Inflammatory Intestines Knowledge Lamina Propria Large Intestine Left Leukocytes Link Mediating Modeling Mus Oral Pathogenesis Pathogenicity Pathway interactions Patients Pharmacology Prevalence Process Publishing Quality of life Reflux Research Role Signal Transduction Site Small Intestines T-Lymphocyte Testing Time Tissues Transgenic Mice Treatment Efficacy United States National Institutes of Health Vomiting airborne allergen early satiety efficacy testing eosinophil experimental study food allergen gastrointestinal genetic approach genetic manipulation human disease immunoregulation in vivo in vivo Model insight migration mouse model notch protein novel prevent psychologic social symptom treatment targeted treatment

项目摘要

Project Summary Eosinophilic gastrointestinal disorders (EGIDs) are a group of inflammatory diseases triggered by food or aero- allergens and characterized by an excessive accumulation and persistence of eosinophils within intestinal tissues and a Th2-dominant immune response. Despite a worldwide increase in prevalence, the natural disease course of EGIDs is unknown, and treatment options limited to food allergen avoidance and oral corticosteroids. EGID symptoms and treatments carry heavy social and psychological tolls, particularly in affected children. Eosinophils are innate immune leukocytes that constitutively home to lamina propria of the small and large intestine in the steady-state. Fundamental factors that govern excessive eosinophil accumulation and persistence within gastrointestinal tissues in EGID patients, and mechanisms whereby intestinal tissue-resident eosinophils might engage food or aero-allergens and participate in EGID pathogenesis remain speculative. At the core of this proposal are our two novel findings that: 1) Identify Notch signaling as a core pathway that orchestrates eosinophil migration and persistence within tissues; and 2) Demonstrate intestinal eosinophils capture intestinal lumen-derived antigen through a process requiring antigen-specific IgG and eosinophil-expressed FcγRIII in vivo, constitutively express antigen presenting cell machinery, and co-localize with T cells following oral allergen challenge. A logical extension of our published and preliminary data, Aim I of this R01 proposal defines the mechanisms whereby Notch signaling regulates eosinophil migration and survival within tissues and tests the efficacies of targeting eosinophil-expressed Notch receptors in preventing EGIDs in vivo. Fully supported by our preliminary data, experiments in Aim II extend our findings that non-IgE humoral immunity provides a direct link between food allergen triggers and tissue eosinophils to test a new paradigm whereby intestinal eosinophils engage in antigen-driven degranulation and direct antigen presenting cell functions that impact the immunopathogenesis of EGIDs by affecting the local repertoire and spatial arrangement of CD4+ T cells. This proposal utilizes a number of genetic manipulations in Aims I and II to systematically test our hypotheses in vivo using three antigenically and anatomically distinct models of EGIDs. In a complementary parallel approach, Aim III utilizes eosinophils isolated from human ileal tissues and humanized transgenic mice to confirm the direct relevance of our data to human disease, and to evaluate the fidelity of the mouse as a model for antigen-driven functions of human intestinal eosinophils.

项目总结