DENDRITIC CELLS IN ATOPIC AND VIRUS-INDUCED AIRWAY DISEASE

特应性和病毒引起的气道疾病中的树突状细胞

基本信息

批准号：
7631199
负责人：
Mitchell H Grayson
金额：
$ 37.88万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-15 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7631199
关键词：
Adoptive Transfer Affinity Allergens Allergic Antigens Antiviral Agents Antiviral Response Asthma Back Binding Cell Differentiation process Cell physiology Cells Chemotactic Factors Data Dendritic Cells Development Disease Exposure to Extrinsic asthma Failure Frequencies Goals Human IgE IgE Receptors Immune response In Vitro Infection Inhalant dose form Interferons Interleukin-10 Interleukin-13 Knowledge Lead Link Lung Mediating Metaplasia Mucous body substance Mus Pathway interactions Phenotype Play Population Prevalence Process Production Recruitment Activity Risk Role Structure of parenchyma of lung T-Lymphocyte Testing Th2 Cells Therapeutic Viral Viral Antigens Virus Virus Diseases atopy base crosslink cytokine in vivo innovation lymph nodes novel public health relevance receptor receptor expression respiratory respiratory infection virus respiratory virus response trafficking

项目摘要

DESCRIPTION (provided by applicant): The prevalence of allergic disease is increasing in the modernized world, with severe respiratory viral infections imparting a greatly increased risk for asthma and allergic (atopic) disease. Viral and allergic diseases induce production of IgE, although no known functional role has been proposed for antiviral IgE. Dendritic cells (DC) are the critical cells initiating the adaptive immune response. The primary goal of this proposal is to understand the role lung parenchyma DC and IgE play in the development of respiratory virus- induced atopic disease. Paramyxoviral infection induces expression of the high affinity receptor for IgE (FceRI) on lung DC, followed by viral specific IgE. This IgE can bind and crosslink FceRI leading to release of a chemoattractant for Th2 and Treg cells. The Th2 cells that are recruited in this manner produce IL-13, which leads to mucous cell metaplasia. Loss of DC FceRI expression led to reduced Th2 and Treg recruitment to the lung and a failure to develop post-viral mucous cell metaplasia. Finally, exposure to a non-viral antigen during the viral infection induced IgE against this non-viral antigen. These data suggest the hypothesis that IgE- mediated crosslinking of FceRI on lung DC leads to recruitment and differentiation of T cells that impart atopy and initiate IgE production against non-viral environmental antigens. To test this hypothesis the following two specific aims are proposed: Aim I. Define the effect of dendritic cell FceRI crosslinking on dendritic and T cell function. In this aim in vitro and in vivo approaches will be utilized to examine the mechanisms by which FceRI alters DC function to lead to the development of a Th2 dependent atopic response. Aim II. Characterize the interdependence between dendritic cell FceRI expression and IgE. In this aim the ability of IgE to modulate FceRI expression on DC will be studied, as will the role of DC FceRI expression to generate IgE against non-viral antigens. PUBLIC HEALTH RELEVANCE. The relevance of these studies is that they provide important knowledge on the mechanisms involved in linking respiratory viral infection to allergic disease and asthma. Further, these studies provide the basis for therapeutic concentration on modulating dendritic cell function to ameliorate post-viral allergic disease and the initial development of asthma and atopy.

描述（由申请人提供）：在现代化世界中，过敏性疾病的患病率正在增加，严重的呼吸道病毒感染大大增加了患哮喘和过敏（特应性）疾病的风险。病毒和过敏性疾病会诱导 IgE 的产生，尽管尚未提出抗病毒 IgE 的已知功能作用。树突状细胞（DC）是启动适应性免疫反应的关键细胞。该提案的主要目标是了解肺实质 DC 和 IgE 在呼吸道病毒诱发的特应性疾病的发展中所发挥的作用。副粘病毒感染诱导肺 DC 上 IgE 高亲和力受体 (FceRI) 的表达，随后是病毒特异性 IgE。这种 IgE 可以结合并交联 FceRI，从而释放 Th2 和 Treg 细胞的趋化剂。以这种方式募集的 Th2 细胞会产生 IL-13，从而导致粘液细胞化生。 DC FceRI表达的丧失导致肺部的Th2和Treg募集减少，并且无法发展病毒后粘液细胞化生。最后，在病毒感染期间接触非病毒抗原会诱导针对该非病毒抗原的 IgE。这些数据表明这样的假设：肺 DC 上 IgE 介导的 FceRI 交联导致 T 细胞的募集和分化，从而赋予特应性并启动针对非病毒环境抗原的 IgE 产生。为了检验这一假设，提出了以下两个具体目标：目标 I. 定义树突状细胞 FceRI 交联对树突状细胞和 T 细胞功能的影响。在此目标中，将利用体外和体内方法来检查 FceRI 改变 DC 功能以导致 Th2 依赖性特应性反应发展的机制。目标二。表征树突状细胞 FceRI 表达与 IgE 之间的相互依赖性。在此目标中，将研究 IgE 调节 DC 上 FceRI 表达的能力，以及 DC FceRI 表达产生针对非病毒抗原的 IgE 的作用。公共卫生相关性。这些研究的相关性在于，它们提供了有关呼吸道病毒感染与过敏性疾病和哮喘之间联系机制的重要知识。此外，这些研究为调节树突状细胞功能以改善病毒后过敏性疾病以及哮喘和特应性的最初发展的治疗浓度提供了基础。