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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.