Initiation and maintenance of adaptive immunity to Mycobacterium tuberculosis

针对结核分枝杆菌的适应性免疫的启动和维持

• 批准号: 7677701
• 负责人: Tyler Dallas Bold
• 金额: $ 4.28万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7677701
• 关键词: Antibiotics; Antigen Presentation; Antigen-Presenting Cells; Antigens; Bacterial Antigens; Cells; Characteristics; Chronic; Chronic Phase; Data; Development; Down-Regulation; Effector Cell; Event; Failure; Future; Gene Expression; Goals; Growth; Human; Immune response; Immunity; Immunology; Individual; Infection; Kinetics; Knowledge; Lung; Maintenance; Mediastinal lymph node group; Mediator of activation protein; Mus; Mycobacterium tuberculosis; Peptides; Population; Property; Proteins; Relative (related person); Respiratory System; Respiratory tract structure; Site; T-Lymphocyte; Testing; Th1 Cells; Tuberculosis; attenuation; design; improved; killings; lymph nodes; novel vaccines; pathogen; respiratory; response; success; therapeutic vaccine; vaccine development

DESCRIPTION (provided by applicant): Despite the availability of antibiotics, tuberculosis remains a major problem worldwide, killing 1.7 million people in 2006. Rational design of an efficacious new vaccine for tuberculosis demands a more complete understanding of the host response to Mycobacterium tuberculosis. The adaptive immune response to M. tuberculosis is crucial for control of bacterial growth, but it cannot eliminate infection. Initiation, expansion, and effector mechanisms of adaptive immunity to this pathogen each rely on the presentation of bacterial peptides to antigen specific T cells, whether to naive T cells in the lung-draining lymph node or to mature Th1 effector cells in the lungs of infected individuals. Therefore, the availability of bacterial antigens and the functional properties of host antigen presenting cells at both of these sites critically determine the success of the adaptive immune response to M. tuberculosis. This proposal has two general goals: 1) To define the cellular events that initiate adaptive immunity to M. tuberculosis, I will characterize the kinetics of M. tuberculosis derived antigen presentation during mouse infection. I will also determine the contribution of individual APC subsets and the relative contribution of M. tuberculosis-infected versus uninfected cells to initiation of adaptive immunity. 2) To identify and quantitate mechanisms that limit the efficacy of the adaptive immune response to M. tuberculosis, I will determine the antigen presentation capability of antigen presenting cells in the lungs of infected mice throughout the course of infection. Furthermore, I will quantitate the contribution of downregulation of Ag85B gene expression by M. tuberculosis during the chronic phase of infection to the inability of adaptive immunity to eradicate M. tuberculosis. These studies will provide an improved understanding of the adaptive immune response to M. tuberculosis, aiding future vaccine development efforts by identifying the critical cell populations and events that initiate adaptive immunity. Elucidation of the shortcomings of endogenous immunity to this successful human pathogen also promises to offer direction to development of therapeutic vaccines and contribute much to the knowledge of the general immunology of' the respiratory tract.

描述（由申请人提供）：尽管抗生素的可用性，结核病仍然是世界范围内的一个主要问题，2006年造成170万人死亡。合理设计一种有效的结核病新疫苗需要更全面地了解宿主对结核分枝杆菌的反应。获得性免疫应答的M。结核病对控制细菌生长至关重要，但它不能消除感染。对该病原体的适应性免疫的起始、扩增和效应器机制各自依赖于细菌肽向抗原特异性T细胞的呈递，无论是向肺引流淋巴结中的幼稚T细胞还是向感染个体的肺中的成熟Th1效应器细胞。因此，细菌抗原的可用性和宿主抗原呈递细胞在这两个位点的功能特性决定了对M的适应性免疫应答的成功。结核该建议有两个总体目标：1）定义启动对M的适应性免疫的细胞事件。结核，我将描述动力学M。小鼠感染过程中结核衍生抗原的呈递。我还将确定单个APC亚群的贡献和M的相对贡献。结核病感染与未感染的细胞启动适应性免疫。2)确定和定量限制对M的适应性免疫应答的功效的机制。结核病，我将确定整个感染过程中感染小鼠肺中抗原呈递细胞的抗原呈递能力。此外，我将定量M.结核病在慢性感染阶段的适应性免疫不能根除M。结核这些研究将提供对M的适应性免疫应答的更好理解。结核病，通过识别启动适应性免疫的关键细胞群和事件来帮助未来的疫苗开发工作。阐明这种成功的人类病原体的内源性免疫的缺点也有望为治疗性疫苗的开发提供方向，并对呼吸道的一般免疫学知识做出很大贡献。