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：
9238657
负责人：
YONGWON CHOI
金额：
$ 20.13万
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 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9238657
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 Reporting Role Route Sampling Signal Transduction Small Intestines Stimulus Symbiosis TRAF6 gene Testing Th2 Cells Time Tissues airway hyperresponsiveness airway inflammation asthmatic asthmatic patient atopy cytokine food antigen germ free condition high risk immunopathology immunoregulation 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（由适用提供）：过敏性哮喘是一种疾病的气道疾病，影响了全球数亿人，并且越来越多地被认为是通过复杂而表现出的，但不了解环境触发器与肺部免疫机制之间的相互作用。更好地了解这些关系对于预防和管理疾病至关重要。兴趣的一个领域是食物过敏和哮喘之间的关系，因为据报道，大约三分之一对食物相关过敏原的反应。食物过敏会影响美国人群的5％，被认为有助于“特应经营”，在一个组织环境中触发抗原遇到的抗原和/或免疫条件可能会随着时间的流逝而导致另一种组织的过敏表现。管理口服抗原敏感性的机制本身是复杂的，并且不足以理解，并且要开发和表征动物模型，这些动物模型可用于识别从口服抗原对过敏性哮喘的敏感性的分子和细胞机制。 We have recently reported generation of a mouse model of sponsorous 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 sponsorous Th2 in the lung in manner that is dependent on food antigen and sensitive to commensal微生物群提出，我们建议研究TRAF6ΔDC作为一种新颖的人类食物抗原相关的过敏性哮喘（在没有可调的）动物模型（在没有可调节的）动物模型中，因此提出了以下具体目的：1。研究TRAF6ΔDC小鼠作为赞助过敏性哮喘的模型。我们将使用家用尘螨抗原抗原F进行诱导的过敏性哮喘方案，使敏感的小鼠经过敏感的小鼠，然后在鼻内挑战。我们将量化气道高敏反应，浸润免疫细胞以及产生的相关细胞因子表达，以确定TRAF6ΔDC小鼠是否暴露了对过敏性哮喘的承诺。此外，我们将确定是否以及如何通过利用GF背景小鼠进行过敏性哮喘诱导来影响DER F诱导的过敏性哮喘的潜在TRAF6ΔDC依赖性影响。 2。研究TRAF6ΔDC小鼠模型中口服抗原和肺免疫病理学之间的关系。我们将使用已经从正常食物饮食转变为无抗原（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，我们将用卵子口服口服的TRAF6ΔDC小鼠，并再次使用卵子进行过敏，并再次通过对Der f Percutcutcutcutcutcutcutcutcutcutatians stercitanes senteransos senteraus senteraus senteransos senteraus senteransos senteraus senteraus senteraus senteransass senteransaus sentanaass senteranatos sentanaass senteranaus senteranaus senteranass senteranaass攻击。最后，我们将对TRAF6ΔDC与对照小鼠的口服OVA-FITC的肠道和肺进行抗原跟踪。