M. tuberculosis Infection in the Lung

肺部结核分枝杆菌感染

基本信息

批准号：
7877766
负责人：
W. Henry Boom
金额：
$ 48.64万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-09-30 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7877766
关键词：
Acute Address Adjuvant Affect Alveolar Macrophages Animals Antigen-Presenting Cells Antigens CD11c Antigens CD3 Antigens CD4 Positive T Lymphocytes Cell physiology Cells Chronic Dendritic Cells Environment Equilibrium Face Failure Generations Genes Genetic Transcription Genus Mycobacterium Growth Histocompatibility Antigens Histocompatibility Antigens Class II Human ITGAX gene Immune Immune response Immunity Infection Invaded Ligands Lipoproteins Lung MHC class II transactivator protein Mediastinal lymph node group Mediating Memory Modeling Mus Mycobacterium Infections Mycobacterium tuberculosis Mycobacterium tuberculosis antigens Organ Outcome Ovalbumin Phase Process Property Pulmonary Tuberculosis Recruitment Activity Relative (related person)Role Site Staging Structure of parenchyma of lung System T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Time Transgenic Mice Tuberculosis Vaccines adaptive immunity antigen processing immune activation improved in vivo insight macrophage memory CD4 T lymphocyte mycobacterial novel pathogen response tuberculosis treatment

项目摘要

DESCRIPTION (provided by applicant): The lung is the primary portal of infection with Mycobacterium tuberculosis (MTB), the cause of human tuberculosis. The ability of MTB to infect and persist in the face of adaptive immunity in the lung is the hallmark of this pathogen. Class II major histocompatibility antigen (MHC-II) restricted CD4+ T cells and their requisite antigen presenting cells (ARC), dendritic cells (DC) and macrophages, are essential for protective immunity. How MHC-II restricted CD4+ T cell responses are generated in the lung during MTB infection is difficult, if not impossible, to address in humans. Murine models of pulmonary MTB infection are well-suited for analysis of the interactions between pulmonary ARC and CD4+ T cells. In addition, mechanisms used by MTB to resist the host and survive in the lung also are readily analyzed in mice. The outcome of the interaction between MTB and CD4+ T cells in the lung is determined by the balance between the lung's ability to optimally process and present MTB antigens for MHC-II restricted CD4+ T cells, and MTB's ability to inhibit CD4+ T cell responses. The relative importance of MTB's activating and inhibitory mechanisms for CD4+ T cells will differ depending on the stage of infection, i.e. early, acute primary vs. chronic persistent infection. There are three specific aims to address this hypothetical model: 1. To determine the ability of lung antigen presenting cells (alveolar macrophages, CD11c+ARC subsets) to activate naive and memory MHC-II restricted CD4+ T cells, and the ability of M. tuberculosis lipoproteins (LpqH, LprA, LprG) and TLR-2 to modulate lung ARC function; 2. To determine the molecules and mechanisms used by M. tuberculosis to directly inhibit naive and effector/memory CD4+ T cell activation and function in the lung; 3. To use CD4+ MTB 85B- and ovalbumin-specific TCR transgenic mice to determine during M. tuberculosis infection the in vivo mechanisms of naive and effector/memory CD4+ T cell activation and the role(s) of lung ARC in this activation. Better understanding of counterbalancing activating and inhibitory immune mechanisms in the lung will provide insight into basic mechanisms of mycobacterial immune evasion and aid in developing improved vaccines and immuno-therapies for tuberculosis.

描述（由申请人提供）：肺是结核分枝杆菌（MTB）的主要感染门户，是人类结核病的原因。 MTB在肺部适应性免疫时感染和持续存在的能力是这种病原体的标志。 II类主要的组织相容性抗原（MHC-II）受限的CD4+ T细胞及其必要的抗原呈现细胞（ARC），树突状细胞（DC）和巨噬细胞对于保护性免疫至关重要。 MHC-II在MTB感染期间在肺中产生的MHC-II限制CD4+ T细胞反应如何在人类中很难解决。肺MTB感染的鼠模型非常适合分析肺弧和CD4+ T细胞之间的相互作用。此外，在小鼠中也很容易分析MTB用来抵抗宿主并在肺中存活的机制。肺中MTB和CD4+ T细胞之间相互作用的结果取决于肺部最佳处理能力与MHC-II限制的CD4+ T细胞的MTB抗原之间的平衡，MTB能够抑制CD4+ T细胞反应的能力。 MTB激活和抑制性机制对CD4+ T细胞的相对重要性将取决于感染阶段，即早期的急性原发性与慢性持续感染。有三个特定的目的是解决这个假设模型：1。确定肺抗原呈递细胞（肺泡巨噬细胞，CD11C+ ARC亚群）激活幼稚和记忆MHC-II受限的CD4+ T细胞的能力，以及结核分枝杆菌lipoproteins（LPQH，LPRA，LPRA，LPRG）和LRC LRC的能力。 2。确定结核分枝杆菌使用的分子和机制直接抑制肺中的天真和效应子/记忆CD4+ T细胞的激活和功能； 3。要使用CD4+ MTB 85b和卵蛋白特异性TCR转基因小鼠在结核分枝杆菌感染期间确定幼稚和效应/记忆/记忆/记忆/记忆CD4+ T细胞活化的体内机制以及该激活中肺弧的作用。更好地理解肺中的反平衡激活和抑制性免疫机制，将洞悉分枝杆菌免疫逃避的基本机制，并有助于开发改进的结核病疫苗和免疫治疗。