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.

项目摘要 嗜酸性粒细胞性胃肠疾病（EGID）是一组由食物或空气引起的炎症性疾病， 过敏原，其特征是肠内嗜酸性粒细胞的过度积累和持续存在。 组织和Th 2-显性免疫应答。尽管世界范围内的流行率增加， EGID的病程尚不清楚，治疗选择仅限于避免食物过敏原和口服 皮质类固醇EGID症状和治疗带来了沉重的社会和心理代价，特别是在 受影响的儿童。嗜酸性粒细胞是先天性免疫白细胞，其组成性地归巢于组织的固有层。 稳定状态下的小肠和大肠。控制嗜酸性粒细胞过多的基本因素 EGID患者胃肠道组织内的蓄积和持久性，以及 肠道组织中的嗜酸性粒细胞可能与食物或空气过敏原结合，并参与EGID 发病机制仍然是推测性的。这个建议的核心是我们的两个新发现：1）识别Notch 信号传导作为协调组织内嗜酸性粒细胞迁移和持久性的核心途径;和2） 证明肠嗜酸性粒细胞通过一个过程捕获肠腔源性抗原， 体内抗原特异性IgG和嗜酸性粒细胞表达的FcγRIII，组成性表达抗原呈递细胞 机械，并与口服过敏原攻击后的T细胞共定位。我们的出版物的逻辑延伸 和初步数据，本R 01提案的目标I定义了Notch信号调节的机制， 组织内嗜酸性粒细胞的迁移和存活，并测试靶向嗜酸性粒细胞表达的Notch 受体在体内预防EGID中的作用。在我们的初步数据的充分支持下，Aim II中的实验扩展了 我们的发现是，非IgE体液免疫提供了食物过敏原触发物和组织之间的直接联系， 嗜酸性粒细胞来测试一种新的范例，其中肠嗜酸性粒细胞参与抗原驱动的脱粒， 直接抗原呈递细胞的功能，通过影响局部免疫系统而影响EGID的免疫发病机制。 CD 4 + T细胞的库和空间排列。这项建议利用了一些遗传操作， 目的I和II使用三种抗原性和解剖学上不同的 EGID模型。在一种互补的平行方法中，Aim III利用从人回肠分离的嗜酸性粒细胞， 组织和人源化转基因小鼠，以证实我们的数据与人类疾病的直接相关性， 评价小鼠作为人肠嗜酸性粒细胞的抗原驱动功能的模型的保真度。