Early Regulation of Immunity in the Respiratory Tract

呼吸道免疫的早期调节

• 批准号: 7019088
• 负责人: Nicole Baumgarth
• 金额: $ 32.63万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7019088
• 关键词: B lymphocyte; antigen presentation; cell migration; cell population study; dendritic cells; developmental genetics; developmental immunology; gene expression; helper T lymphocyte; immunoregulation; influenzavirus A; laboratory mouse; leukocyte activation /transformation; lymph nodes; mixed tissue /cell culture; mucosal immunity; passive immunization; respiratory infections; respiratory system; virus infection mechanism

DESCRIPTION (provided by applicant): The respiratory tract is one of the most important sites of entry for pathogens including many potential bioterrorism agents such as influenza virus. Although local innate and early adaptive immune defenses are known to be crucial for limiting initial pathogen spread, the mechanisms underlying mucosal immunity in the respiratory tract are still poorly defined. Lung tissue dendritic cells (DC) are key components of the innate immune system that regulate adaptive immunity by migrating to the regional lymph nodes to present antigens to T cells. Preliminary data suggest that contrary to current dogma, DC can also activate immune responses in the lung tissue itself. The objective of this application is to determine the mechanisms by which respiratory tract DC activated by influenza virus-infection regulate local virus-specific T and B cell responses and to test how application of inactivated virus (as a prototype vaccine) affects their functions. The central hypothesis underlying this study is that infection of lung tissue DC is critical for their ability to present antigen to B cells and to regulate virus-specific CD4 T cell responses. The following Specific Aims are proposed: Specific Aim #1 is to fully characterize respiratory tract DC responses following sublethal infection of mice with influenza A/PR8, by studying the phenotype of DC and their viral- and host-gene expression ex vivo and to determine the mechanisms by which they regulate virus-specific T-dependent and/or T-independent B cell responses. Specific Aim #2 will determine the ability of lung tissue and draining lymph node DC to regulate the induction and/or quality of virus-specific effector CD4 T cell responses, by measuring cytokine profiles and clonal burst sizes of naive and activated CD4+T cells in co-cultures with virus-stimulated respiratory tract DC and in vivo following adoptive transfer of DC. Specific Aim #3 is to determine whether application of inactivated virus induces local DC populations that differ in phenotype, gene expression profile or effector function from those induced by live virus infection; thus whether differences in the quality of the DC responses induced to live and inactivated virus could underlie the often disappointing levels of protection achieved with inactivated virus vaccines compared to those obtained after active infection. In summary, this study will provide a detailed understanding of respiratory tract DC biology, particularly their role in regulating early local responses at the site of pathogen entry. This information could help the development of novel interventions that utilize early respiratory tract defenses for immune protection.

描述（由申请人提供）：呼吸道是病原体最重要的进入部位之一，包括许多潜在的生物恐怖剂，例如流感病毒。尽管已知局部先天性和早期适应性免疫防御对于限制初始病原体传播至关重要，但呼吸道粘膜免疫的机制仍不清楚。肺组织树突状细胞 (DC) 是先天免疫系统的关键组成部分，通过迁移到区域淋巴结向 T 细胞呈递抗原来调节适应性免疫。初步数据表明，与目前的教条相反，DC 还可以激活肺组织本身的免疫反应。本应用的目的是确定流感病毒感染激活的呼吸道 DC 调节局部病毒特异性 T 和 B 细胞反应的机制，并测试灭活病毒（作为原型疫苗）的应用如何影响其功能。这项研究的核心假设是，肺组织 DC 的感染对于它们向 B 细胞呈递抗原和调节病毒特异性 CD4 T 细胞反应的能力至关重要。提出以下具体目标： 具体目标 #1 是通过离体研究 DC 的表型及其病毒和宿主基因表达，全面表征 A/PR8 型流感小鼠亚致死感染后呼吸道 DC 的反应，并确定它们调节病毒特异性 T 依赖性和/或 T 非依赖性 B 细胞反应的机制。具体目标#2将通过测量初始和活化CD4+T细胞的细胞因子谱和克隆爆发大小来确定肺组织和引流淋巴结DC调节病毒特异性效应CD4T细胞反应的诱导和/或质量的能力与病毒刺激的呼吸道 DC 共培养以及 DC 过继转移后的体内。具体目标#3是确定应用灭活病毒是否会诱导局部DC群体在表型、基因表达谱或效应子功能上与活病毒感染诱导的DC群体不同；因此，DC对活病毒和灭活病毒的反应质量的差异是否可能是灭活病毒疫苗与活性感染后获得的保护水平经常令人失望的基础。总之，这项研究将提供对呼吸道 DC 生物学的详细了解，特别是它们在调节病原体进入部位的早期局部反应中的作用。这些信息可以帮助开发利用早期呼吸道防御来进行免疫保护的新型干预措施。