"The Tuberculous Granuloma"

该项目的总体目标是开发新的、安全和有效的结核分枝杆菌(Mtb)- 用于预防结核病(TB)的衍生疫苗。项目3将重点调查两个角色 结核肉芽肿的成分-B细胞和肿瘤坏死因子(TNF)-在它们的能力 增强抗结核疫苗的免疫原性。拟议的方案是从上一年生成的数据派生的 资助期。B细胞缺陷)j.MT小鼠的研究表明，这些淋巴细胞是 急性结核病的最佳控制。在慢性感染中，IMT中的T细胞反应(增殖和IFNy产生) 老鼠被显著地改变了。利用缺乏特异性Fey受体(FcyR)的小鼠进行的研究提供了 免疫复合体(IC)可调节抗结核细胞免疫的证据。这些都是令人信服的证据 B细胞在结核病感染中可以调节T细胞反应。此外，一种有效的污垢分枝杆菌皮肤病疫苗 IKEPLUS虽然在免疫野生型小鼠抵抗结核分枝杆菌攻击方面非常有效，但未能保护B细胞- 有缺陷的动物。项目3将描述B细胞在发展抗结核免疫和 为了检验以下假设：i)B细胞的特定功能对宿主免疫有显著贡献 对结核分枝杆菌的反应；ii)B细胞是发展结核病有效T细胞反应所必需的，包括 CD4T细胞记忆隔间；iii)B细胞对于最佳疫苗的开发至关重要-- 产生的保护；以及iv)IC可被利用来增强抗结核免疫。在肿瘤坏死因子研究中，我们有 鉴定出能够下调巨噬细胞肿瘤坏死因子产生的结核分枝杆菌核心克隆。我们将测试 假设肿瘤坏死因子下调基因的破坏将产生能够增强的菌株 巨噬细胞在感染过程中产生肿瘤坏死因子，从而通过其能力增强免疫原性 促进吞噬小体成熟和细胞凋亡，这两个过程可以增强T细胞免疫。总而言之。 项目3试图确定B细胞反应和肿瘤坏死因子下调结核分枝杆菌基因的成分，这些成分可以 增强候选疫苗的免疫原性。一旦确定，这些组件将被合并 到现有的安全有效的MTB衍生平台(在上一个供资期间开发)，以进一步 提高候选抗结核疫苗的效力，这是P01的总体目标。因此，会有近距离的 项目3与项目计划的其他组成部分之间的互动。最后，动物，流动 细胞仪和管理核心都将被项目3中提议的计划广泛利用。 相关性(请参阅说明)： 项目3是POL的组成部分，旨在确定B细胞免疫和肿瘤坏死因子- 下调可靶向增强宿主对结核分枝杆菌的免疫力的基因。此类产品的识别 这些因素将指导安全有效的结核分枝杆菌减毒疫苗候选疫苗的基本设计 高水平的免疫原性，可以有效地产生对结核杆菌的保护。

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.