"The Tuberculous Granuloma"

本计划项目的总体目标是开发新型、安全、有效的M。结核病（Mtb）- 用于预防结核病（TB）的衍生疫苗。项目3将重点调查两个机构的作用， 结核性肉芽肿的组成部分- 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。所提出的程序来自最后生成的数据， 融资期。B细胞缺陷的μMT小鼠研究表明，这些淋巴细胞是免疫调节所必需的。 急性结核病的最佳控制。在慢性感染中，μMT中的T细胞应答（增殖和IFN γ产生） 老鼠有了显著的改变。使用特异性Fc γ受体（Fc γ R）缺陷的小鼠的研究已经提供了 免疫复合物（IC）可调节抗TB细胞免疫的证据。这些都是有力的证据 B细胞可以调节TB感染中的T细胞应答。此外，一个强大的M。包皮垢疫苗 IKEPLUS虽然在免疫野生型小鼠对抗Mt B攻击方面非常有效，但未能保护B细胞。 缺陷动物项目3将描述B细胞在抗结核免疫发展中的作用， i）B细胞的特异性功能显著促进宿主免疫应答， ii）B细胞是TB中产生有效T细胞应答所必需的，包括 ⑶ 4 T细胞记忆区室; iii）B细胞对于最佳疫苗的开发是必需的- 产生的保护;和iv）IC可用于增强抗TB免疫。在TNF研究中， 鉴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-下调基因的破坏将产生能够增加 感染期间巨噬细胞TNF的产生，从而凭借其 促进吞噬体成熟和凋亡，这两个过程可以增强T细胞免疫。总之。 项目3旨在确定B细胞反应的组分和TNF下调Mt B基因， 增强候选疫苗的免疫原性。这些组成部分一旦确定， 现有的安全有效的结核衍生平台（在上一个供资期开发），以进一步 增强候选抗结核疫苗的效力，是P01的总体目标。因此，将有密切的 项目3与项目计划其他组成部分之间的相互作用。最后，动物，流动 细胞计数和管理核心都将被项目3中提出的项目广泛使用。

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 of the 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 μMT 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 μMT 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-derived 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 of the P01. Thus, there will be close interactions between Project 3 and the other components of the Program Project. Finally, the Animal, Flow Cytometry, and Administrative Cores will all be utilized extensively by the program proposed in Project 3.