Dendritic Cell-Mediated Oral Antigen Tolerance and the Lung

树突状细胞介导的口腔抗原耐受和肺

基本信息

批准号：
9086712
负责人：
YONGWON CHOI
金额：
$ 24.1万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-07 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9086712
关键词：
Adjuvant Affect Allergens Allergic Animal Model Antigens Area Asthma Breathing Cell physiology Cells Child Complex Data Defect Dendritic Cells Dermatophagoides Antigens Development Diet Disease Disease Management Effector Cell Environment Exhibits Exposure to Extrinsic asthma Fluorescein-5-isothiocyanate Food Food Hypersensitivity Generations Germ-Free Human Hypersensitivity Immune Immune System Diseases Immune Tolerance Immune response Immunity Immunologics Infection Infiltration Intestines Lead Lung Mediating Mediator of activation protein Methods Modeling Molecular Mus Oral Pathologic Play Population Predisposition Prevention Process Protocols documentation Reaction Regulation Reporting Role Route Sampling Signal Transduction Small Intestines Stimulus TRAF6 gene Testing Th2 Cells Time Tissues airway hyperresponsiveness airway inflammation asthmatic asthmatic patient atopy cytokine food antigen germ free condition high risk immunopathology interest microbiota mouse model novel public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Allergic asthma is a disease of the airway that affects hundreds of millions of people worldwide, and that is increasingly recognized as manifesting via complex, but poorly understood interactions between environmental triggers and immunologic mechanisms within the lung. Better understanding these relationships is critical for prevention and management of disease. One area of emerging interest is the relationship between food allergy and asthma, as it has been reported that roughly a third of children with food allergy develop asthma, and that patients with both conditions exhibit significantly higher risk of a fatal reaction to food-related allergens. Food allergy affects an estimated 5% of the U.S. population and is believed to contribute to "atopic march", in which triggering antigens encountered and/or immunologic conditions in one tissue environment may contribute over time to allergic manifestations in another. The mechanisms governing oral antigen sensitivity are themselves complex and insufficiently understood, and it would be of considerable value to develop and characterize animal models that can be used to identify the molecular and cellular mechanisms underpinning atopic march from oral antigen sensitivity to allergic asthma. We have recently reported generation of a mouse model of spontaneous eosinophilic Th2-associated disease of the small intestine called TRAF6ΔDC, in which dendritic cell (DC)-intrinsic expression of the signaling mediator TRAF6 is ablated, and now present preliminary data that TRAF6ΔDC also exhibit spontaneous Th2 in the lung in manner that is dependent on food antigen and sensitive to commensal microbiota Thus, we propose investigating TRAF6ΔDC as a novel spontaneously occurring (in the absence of adjuvant) animal model of human food antigen-associated allergic asthma, and therefore propose the following specific aims: 1. Investigate TRAF6ΔDC mice as a model for spontaneous allergic asthma. We will subject TRAF6ΔDC mice to an induced allergic asthma protocol using house dust mite antigen Der f to sensitize mice percutaneously and then challenge intranasally. We will quantify airway hypersensitivity responses, infiltrating immune cells and related cytokine expression produce in order to determine whether TRAF6ΔDC mice exhibit propensity toward allergic asthma. Additionally, we will determine whether and how potential TRAF6ΔDC-dependent effects on Der f-induced allergic asthma may be affected by utilizing GF background mice for allergic asthma induction. 2. Investigate the relationship between oral antigen and lung immunopathology in the TRAF6ΔDC mouse model. We will perform allergic asthma induction using Der f sensitization with TRAF6ΔDC mice that have been transitioned from normal chow diet to antigen-free (AF) diet. To test whether model antigen, encountered via the oral route, is capable of inducing or exacerbating allergic asthma in TRAF6∆DC mice, we will orally gavage AF-transitioned TRAF6∆DC mice with OVA, and again test allergic asthma in response to Der f percutaneous sensitization and intranasal challenge. Finally, we will perform antigen tracking to the gut and lung of oral OVA-FITC in TRAF6∆DC versus control mice.

描述（由申请人提供）：过敏性哮喘是一种气道疾病，影响着全世界数亿人，人们越来越认识到这种疾病是通过环境触发因素和肺内免疫机制之间复杂但知之甚少的相互作用表现出来的。这些关系对于疾病的预防和管理至关重要，其中一个新兴领域是食物过敏与哮喘之间的关系，据报道，大约三分之一的食物过敏儿童会患上哮喘，并且患有这两种疾病的患者。表现出明显更高的风险致命的对食物相关过敏原的反应估计影响了 5% 的美国人口，并被认为会导致“特应性行军”，其中在一种组织环境中触发抗原和/或免疫状况可能会随着时间的推移导致过敏表现。另一方面，控制口腔抗原敏感性的机制本身很复杂且尚未得到充分了解，开发和表征可用于识别从口腔抗原敏感性到特应性变态反应的分子和细胞机制的动物模型将具有相当大的价值。我们最近报道了一种名为 TRAF6ΔDC 的自发性 Th2 相关小肠疾病的小鼠模型，其中信号传导介质 TRAF6 的树突状细胞 (DC) 固有表达被消除，现在提供初步数据TRAF6ΔDC 还在肺中以依赖于食物抗原且对共生微生物敏感的方式表现出自发性 Th2。因此，我们建议将 TRAF6ΔDC 作为一种新型自发发生的研究进行研究（在没有佐剂的情况下）人类食物抗原相关过敏性哮喘的动物模型，因此提出以下具体目标： 1.研究TRAF6ΔDC小鼠作为自发性过敏性哮喘模型我们将对TRAF6ΔDC小鼠进行诱导过敏性哮喘方案。使用屋尘螨抗原 Der f 经皮致敏，然后鼻内激发，我们将量化气道过敏反应、浸润免疫细胞和相关细胞因子表达的产生，以确定是否产生。 TRAF6ΔDC 小鼠表现出过敏性哮喘倾向。此外，我们将确定使用 GF 背景小鼠进行过敏性哮喘诱导是否以及如何影响 TRAF6ΔDC 潜在的效应。 TRAF6ΔDC 小鼠模型中的肺部免疫病理学我们将使用 Der f 致敏对已从正常饮食转变为无抗原 (AF) 饮食的 TRAF6ΔDC 小鼠进行过敏性哮喘诱导。为了测试通过口服途径遇到的模型抗原是否能够在 TRAF6ΔDC 小鼠中诱导或加剧过敏性哮喘，我们将用 OVA 口服强饲 AF 转化的 TRAF6ΔDC 小鼠，并再次测试对 Der f 的过敏性哮喘反应。最后，我们将在 TRAF6ΔDC 与对照小鼠中对口服 OVA-FITC 的肠道和肺部进行抗原追踪。