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

• 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
• 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

 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与肺内免疫机制之间复杂但知之甚少的相互作用而表现出来的。更好地理解这些关系对于疾病的预防和管理至关重要。一个新兴的兴趣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显着更高的致命风险 对食物相关过敏原的反应。据估计，食物过敏影响了 5% 的美国人口，并被认为会导致“特应性游行”，其中触发一种组织环境中遇到的抗原和/或免疫状况，随着时间的推移，可能会导致另一种组织环境中的过敏表现。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过敏性哮喘的特应性进展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 的自发性嗜酸性粒细胞性 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，现在提供的初步数据表明，TRAF6ΔDC 也在肺中以依赖于食物抗原和对共生体敏感的方式表现出自发性 Th2 因此，我们建议研究TRAF6ΔDC作为人类食物抗原相关过敏性哮喘的新型自发（无佐剂）动物模型，并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 经皮致敏小鼠，然后鼻内攻击。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 TRAF6ΔDC 小鼠是否表现出过敏性哮喘倾向。此外，我们将确定是否以及如何通过利用 GF 背景小鼠诱导过敏性哮喘来影响 Der f 诱导的过敏性哮喘的潜在 TRAF6ΔDC 依赖性效应。 2. 在TRAF6ΔDC小鼠模型中研究口服抗原与肺免疫病理学之间的关系。我们将使用 Der f 致敏法对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诱导或加剧 TRAF6ΔDC 小鼠的过敏性哮喘，我们将用 OVA 口服强饲 AF 转化的 TRAF6ΔDC 小鼠，并再次测试对 Der f 经皮致敏和鼻内激发的过敏性哮喘反应。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。