"The Tuberculous Granuloma"

《结核性肉芽肿》

• 批准号: 8049857
• 负责人: John R. Chan
• 金额: $ 34.59万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8049857
• 关键词: Acute; Animals; Antigen-Antibody Complex; Antitubercular Agents; Apoptosis; Attenuated Vaccines; B-Lymphocytes; Bacillus (bacterium); Cellular Immunity; Chronic; Data; Development; Flow Cytometry; Funding; Genes; Goals; Granuloma; Granulomatous; Host Defense; Immune response; Immunity; Infection; Instruction; Investigation; Lymphocyte; Molecular Analysis; Mus; Mycobacterium smegmatis; Mycobacterium tuberculosis; Phagosomes; Play; Prevention; Process; Production; Role; Sum; T cell response; T-Lymphocyte; Testing; Tuberculosis; Tuberculosis Vaccines; Tumor Necrosis Factor-alpha; Vaccines; design; human TNF protein; immunogenicity; macrophage; memory CD4 T lymphocyte; novel; programs; receptor; response; tuberculosis immunity; vaccine candidate

The overall goal of this Program Project is to develop novel, safe, and effective M. tuberculosis (Mtb)- derived vaccines for the prevention of tuberculosis (TB). Project 3 will focus on investigating the roles of two components ofthe tuberculous granuloma - B cells and tumor necrosis factor (TNF) - in their ability to augment Immunogenicity of anti-TB vaccines. The proposed program derives from data generated in the last funding period. The B cell-deficient )j.MT mouse studies revealed that these lymphocytes are required for the optimal control of acute TB. In chronic infection, T cell response (proliferation and IFNy production) in ^iMT mice Is remarkably altered. Studies using mice deficient in specific Fey receptors (FcyR) have provided evidence that immune complex (IC) can modulate anti-TB cellular immunity. These are compelling evidence that B cells can regulate T cell response in TB infection. Further, a potent M. smegmatis-derwed vaccine IKEPLUS, while highly effective in immunizing wildtype mice against Mtb challenge, failed to protect B cell- deficient animals. Project 3 will characterize the roles of B cells in the development of anti-TB immunity and to test the hypotheses that: i) Specific functions of B cells contribute significantly to the host immune response to Mtb; ii) B cells are required for the development of effective T cell response in TB, including the CD4 T cell memory compartment; iii) B cells are essential for the development of optimal vaccine- engendered protection; and iv) IC can be exploited to augment anti-TB immunity. In the TNF study, we have identified Mtb cosimd clones capable of downregulating macrophage TNF production. We will test the hypothesis that disruption of the TNF-downregulating genes will generate strains that are able to augment macrophage TNF production during infection, thereby enhancing immunogenicity by virtue of their ability to promote phagosome maturation and apoptosis, two processes that can augment T cell immunity. In sum. Project 3 seeks to identify components of the B cell response and TNF-downregulating Mtb genes that can augment immunogenicity of vaccine candidates. These components, when identified, will be incorporated into existing safe and effective Mtb-derived platforms (developed In the last funding period) to further enhance the efficacy of candidate anti-TB vaccines, the overall goal ofthe P01. Thus, there will be close interactions between Project 3 and the other components ofthe Program Project. Finally, the Animal, Flow Cytometry, and Administrative Cores will all be utilized extensively by the program proposed in Project 3. RELEVANCE (See instructions): Project 3, an integral part of the POl, seeks to identify components of B cell immunity and TNF- downregulating genes that can be targeted to enhance host Immunity against Mtb. Identificaion of such factors will guide the rationale design of safe and effective Mtb-derived attenuated vaccine candidates with high level of immunogenicity that can effectively engender protection against the tubercle bacillus.

该计划项目的总体目标是开发新颖，安全和有效的结核分枝杆菌（MTB） - 预防结核病（TB）的衍生疫苗。项目3将重点介绍两个 结核性肉芽肿的成分 - B细胞和肿瘤坏死因子（TNF）的成分 - 抗TB疫苗的增强免疫原性。提出的程序源自上次生成的数据 资金期。 B细胞缺陷）J.MT小鼠研究表明，这些淋巴细胞是必需的 急性结核病的最佳控制。在慢性感染中，T细胞反应（增殖和IFNY产生） 小鼠发生了极大的改变。使用缺乏特定FEY受体（FCYR）的小鼠的研究已提供 免疫复合物（IC）可以调节抗TB细胞免疫的证据。这些是令人信服的证据 该B细胞可以调节结核病感染中的T细胞反应。此外，一种有效的M. Smegmatis脱水疫苗 ikeplus虽然在对MTB挑战中进行免疫野生型小鼠的免疫效果，但未能保护B细胞 动物不足。项目3将表征B细胞在抗TB免疫发展和 测试以下假设：i）B细胞的特定功能对宿主免疫有显着贡献 对MTB的反应； ii）B细胞在结核病中发展有效T细胞反应需要B细胞，包括 CD4 T细胞存储器室； iii）B细胞对于开发最佳疫苗至关重要。 获得保护； iv）可以利用IC来增强抗TB免疫。在TNF研究中，我们有 确定了能够下调巨噬细胞TNF产生的MTB COSIMD克隆。我们将测试 假设TNF降低基因的破坏将产生能够增加的菌株 巨噬细胞在感染过程中产生巨噬细胞，从而增强免疫原性 促进吞噬体成熟和凋亡，这两个过程可以增强T细胞免疫。总结。 项目3旨在确定B细胞响应的组成部分和tnf下调的MTB基因 候选疫苗的免疫原性增强。确定这些组件将被合并 进入现有的安全有效的MTB衍生平台（在最后一个资金期间开发）以进一步 提高候选抗TB疫苗的功效，这是P01的总体目标。因此，会很近 项目3与计划项目的其他组件之间的交互。最后，动物流动 细胞仪和行政核心将被项目3中提出的程序广泛利用。 相关性（请参阅说明）： 项目3是POL的组成部分，旨在鉴定B细胞免疫和TNF-的组成部分 下调可以针对旨在增强宿主免疫力的基因。确定了这种情况 因素将指导安全有效的MTB衍生的疫苗候选疫苗的基本原理设计 高水平的免疫原性可以有效地保护结核菌。