Dendritic Cell-Mediated Oral Antigen Tolerance and the Lung

 描述（由申请人提供）：过敏性哮喘是一种影响全世界数亿人的气道疾病，并且越来越多地被认为是通过复杂但知之甚少的环境触发因素与肺内免疫机制之间的相互作用表现的。更好地了解这些关系对于预防和管理疾病至关重要。一个新出现的感兴趣的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发展为哮喘，并且患有这两种疾病的患者表现出明显更高的致命性哮喘的风险。 对食物相关过敏原的反应。食物过敏影响估计5%的美国人口，并且被认为有助于“特应性行进”，其中在一种组织环境中遇到的触发抗原和/或免疫学条件可能随着时间的推移导致另一种组织环境中的过敏表现。控制口服抗原敏感性的机制本身是复杂的，而且还没有得到充分的理解，开发和表征动物模型将具有相当大的价值，这些动物模型可用于鉴定支持从口服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。我们最近报道了一种称为TRAF 6 ΔDC的自发性小肠嗜酸性Th 2相关疾病的小鼠模型的产生，其中树突状细胞（DC）内在表达的信号介质TRAF 6被消融，现在提出的初步数据表明TRAF 6 ΔDC也以依赖于食物抗原和对肠道微生物群敏感的方式在肺中表现出自发性Th 2。我们建议研究TRAF 6 ΔDC作为一种新的自发发生的（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的：1.研究TRAF 6 ΔDC小鼠作为自发性过敏性哮喘模型。我们将TRAF 6 ΔDC小鼠进行诱导过敏性哮喘方案，使用屋尘螨抗原Der f致敏小鼠，然后鼻内激发。我们将量化气道超敏反应、浸润免疫细胞和相关细胞因子表达产物，以确定TRAF 6 ΔDC小鼠是否表现出变应性哮喘的倾向。此外，我们将确定是否以及如何通过使用GF背景小鼠进行过敏性哮喘诱导来影响TRAF 6 Δ DC对Der f诱导的过敏性哮喘的潜在依赖性作用。2.在TRAF 6 ΔDC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致敏对TRAF 6 ΔDC小鼠进行过敏性哮喘诱导，这些小鼠已从正常饲料饮食过渡到无抗原（AF）饮食。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重TRAF 6 β DC小鼠中的过敏性哮喘，我们将用OVA口服管饲AF转化的TRAF 6 β DC小鼠，并再次测试响应于Der f经皮致敏和鼻内激发的过敏性哮喘。最后，我们将在TRAF 6 PDDC与对照小鼠中对口服OVA-FITC的肠和肺进行抗原追踪。

 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.