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

• 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
• 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

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.

项目概要 嗜酸粒细胞性胃肠道疾病（EGID）是一组由食物或空气引发的炎症性疾病。 过敏原，其特征是肠道内嗜酸性粒细胞过度积累和持续存在 组织和 Th2 主导的免疫反应。尽管在世界范围内患病率有所增加，但自然 EGID 的病程尚不清楚，治疗方案仅限于避免食物过敏原和口服 皮质类固醇。 EGID 症状和治疗会造成严重的社会和心理损失，特别是在 受影响的儿童。嗜酸性粒细胞是固有免疫白细胞，其本质上是细胞固有层的家园。 小肠和大肠处于稳态。控制嗜酸性粒细胞过多的基本因素 EGID 患者胃肠组织内的积累和持久性及其机制 肠道组织中的嗜酸性粒细胞可能与食物或空气过敏原接触并参与 EGID 发病机制仍存在推测。该提案的核心是我们的两个新颖发现：1）识别缺口 信号传导作为协调嗜酸性粒细胞在组织内迁移和持久存在的核心途径；和 2) 证明肠道嗜酸性粒细胞通过一个需要捕获肠腔衍生抗原的过程 体内抗原特异性IgG和嗜酸性粒细胞表达的FcγRIII，组成型表达抗原呈递细胞 机械，并在口腔过敏原挑战后与 T 细胞共定位。我们已发布的逻辑扩展 和初步数据，该 R01 提案的目标 I 定义了 Notch 信号传导调节的机制 嗜酸性粒细胞在组织内的迁移和存活，并测试靶向嗜酸性粒细胞表达的 Notch 的功效 受体在体内预防 EGIDs。 Aim II 中的实验得到了我们初步数据的充分支持 我们的研究结果表明，非 IgE 体液免疫在食物过敏原触发因素和组织之间提供了直接联系 嗜酸性粒细胞测试一种新的范例，其中肠道嗜酸性粒细胞参与抗原驱动的脱粒和 直接抗原呈递细胞功能，通过影响局部抗原来影响 EGID 的免疫发病机制 CD4+ T 细胞的库和空间排列。该提案利用了许多基因操作 目标 I 和 II 使用三种抗原性和解剖学上不同的方法在体内系统地检验我们的假设 EGID 模型。在互补的并行方法中，Aim III 利用从人回肠中分离的嗜酸性粒细胞 组织和人源化转基因小鼠，以确认我们的数据与人类疾病的直接相关性，并 评估小鼠作为人类肠道嗜酸性粒细胞抗原驱动功能模型的保真度。