Mechanisms by Which Influenza A Protects Against Asthma

甲型流感预防哮喘的机制

• 批准号: 7449665
• 负责人: DALE T UMETSU
• 金额: $ 43.95万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-15 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7449665
• 关键词: Affect; Allergens; Antigens; Asthma; Breathing; California; Cell physiology; Cells; Dendritic Cells; Development; Disease Progression; Doctor of Philosophy; Environment; Exposure to; Goals; Immune response; Immunity; Infection; Influenza; Influenza A virus; Laboratories; Learning; Lung; Mus; Numbers; Personal Satisfaction; Phenotype; Pneumonia; Population; Positioning Attribute; Reagent; Role; Suppressor-Effector T-Lymphocytes; System; T-Cell Activation; T-Lymphocyte; Transgenic Mice; Universities; Virus Diseases; Week; airway hyperresponsiveness; airway inflammation; experience; in vivo; influenzavirus; prevent; pulmonary function; research study; respiratory; response; tool

DESCRIPTION (provided by applicant): The overall goal of the proposed studies is to understand how infection with influenza A virus inhibits disease progression in asthma. Our hypothesis is that infection with influenza A virus alters the pulmonary environment and enhances the development of protective immune responses to allergens inhaled 2-4 weeks after infection. We believe that infection with influenza virus can in some situations promote "protective" immunity by the altering dendritic cell (DC) function in, and the cellular composition of the lungs, in a way that enhances the development of regulatory/suppressor cells, which inhibit the pulmonary bias towards Th2 sensitization, and which inhibit the development of airway hyperreactivity (AHR), asthma exacerbations and disease progression. Our laboratory is well positioned to perform these studies, because we have examined allergen-induced AHR in mice for many years, and have acquired a large number of tools and reagents to study many parameters of airway inflammation. We have examined the role of pulmonary dendritic cells (DCs), including CD8alpha- and CD8alpha+ subsets of DCs, and antigen- specific CD4+ regulatory T cells in AHR, and have defined the parameters required for their development. In addition, we were the first to demonstrate a major role for NKT cells in the development of AHR, and have a large number of reagents to study NKT cells (CD1d tetramers, NKT cell deficient and NKT cell transgenic mice, and expertise to purify and adoptively transfer NKT cells). Finally, we have previously shown that infection with influenza A virus followed 2-4 wks later by respiratory exposure to allergen results in an immune response that protects against AHR. We now propose to examine how influenza A infection alters the function of pulmonary DCs, NKT cells and the development of regulatory T cells that inhibit AHR. Dr. Nicole Baumgarth, DVM, PhD, (University of California, Davis) has extensive experience in the study of influenza virus, and will assist us with these experiments. By understanding the specific mechanisms by which influenza affects the lung, we will develop a much greater understanding of immune responses that protect against Th2 inflammation and pulmonary exacerbations. We will also learn more about regulatory mechanisms that affect airway inflammation, and how viral infections and the environment affect the development of asthma.

描述（由申请人提供）： 拟议研究的总体目标是了解流感A病毒感染如何抑制哮喘中疾病进展。 我们的假设是，流感病毒感染会改变肺部环境，并增强感染后2-4周吸入过敏原的保护性免疫反应的发展。 我们认为，在某些情况下，流感病毒感染可以通过改变的树突状细胞（DC）功能和肺的细胞组成来促进“保护性”免疫，从而增强调节/抑制细胞的发展，从而抑制调节/抑制细胞的发展。肺部对Th2敏化的偏见，并抑制气道高反应性的发展 （AHR），哮喘加剧和疾病进展。 我们的实验室可以很好地进行这些研究，因为我们已经检查了多年的小鼠过敏原诱导的AHR，并且已经获得了大量工具和试剂来研究气道炎症的许多参数。 我们已经检查了肺树突状细胞（DC）的作用，包括DC的CD8Alpha-和cd8alpha+亚群，以及AHR中抗原 - 特异性CD4+调节T细胞，并定义了其发育所需的参数。 此外，我们是第一个证明NKT细胞在AHR发展中起主要作用的人，并且具有大量研究NKT细胞的试剂（CD1D四聚体，NKT细胞缺乏和NKT细胞转基因小鼠，以及用于纯化和纯化和纯化和纯化和专业知识继而转移NKT细胞）。 最后，我们先前已经表明，流感A病毒感染随后2-4周，呼吸道暴露于过敏原导致免疫反应可预防AHR。 现在，我们建议检查流感A感染如何改变肺DC，NKT细胞的功能以及抑制AHR的调节性T细胞的发展。 DVM博士（加利福尼亚大学戴维斯大学）的Nicole Baumgarth博士在流感病毒研究方面拥有丰富的经验，并将为我们提供这些实验。 通过了解流感影响肺部的特定机制，我们将对可以预防TH2炎症和肺部恶化的免疫反应有更大的了解。 我们还将了解更多有关影响气道炎症的调节机制，以及病毒感染和环境如何影响哮喘的发展。