CONTACT-MEDIATED HOST RESISTANCE TO M TUBERCULOSIS

描述 结核病仍然是一个巨大的国际卫生问题， 由于目前世界上有三分之一的人口感染了 致病微生物，结核分枝杆菌。细胞免疫， 涉及致敏淋巴细胞与M。 感染了结核病的单核巨噬细胞，可以含有这种有机体， 结果发现，绝大多数原本健康的人 个人在感染后不会发展为活动性结核病。 艾滋病毒阳性的人极大地增加了对 结核分枝杆菌感染后活动性疾病的发展。 此外，肺结核通常是艾滋病毒感染的早期并发症。 这是CD4+T细胞数量显著下降的先兆。与之形成鲜明对比的是 其他细胞内病原体的研究，体外激活添加 细胞因子并不能显著减少细胞内的生长 结核分枝杆菌。利用一种人类定量感染的方法 单核吞噬细胞伴有致病性结核分枝杆菌 淋巴细胞与这些感染细胞的相互作用可以被表征， 初步研究表明，将淋巴细胞加入到M。 结核感染的单核细胞在限制细胞内的方面更有效 生长比这些文化的培养上清液的转移更重要。它是 假设细胞与细胞之间的接触涉及 特定的细胞表面分子是最大限度地激活人类所必需的 单核巨噬细胞抑制结核分枝杆菌的细胞内生长。 这一假设将在以下具体目标中得到解决：1) 确定抗原特异性CD4+的接触依赖机制 T细胞激活结核分枝杆菌感染的杀菌功能 单核吞噬细胞；2)测定最大CD4+T细胞介导的 激活结核分枝杆菌感染的单核吞噬细胞需要 细胞接触和细胞因子产生的顺序或交互作用； 3)检测CD8+T细胞、Gammadelta T细胞和NK细胞 结核分枝杆菌感染单核细胞的介导性接触激活 吞噬细胞，以比较这些效应者群体使用的机制 CD4+T细胞的表达，并确定Fas/FasL的作用 人体内结核分枝杆菌杀伤的细胞毒效应机制 单核巨噬细胞。

DESCRIPTION Tuberculosis remains an international health problem of immense proportions, as one-third of the world's population is currently infected with the causative organism, Mycobacterium tuberculosis. Cell-mediated immunity, involving the interaction of sensitized lymphocytes with M. tuberculosis-infected mononuclear phagocytes, can contain the organism, resulting in the finding that the great majority of otherwise healthy individuals do not develop active tuberculosis following infection. HIV-positive individuals have greatly increased susceptibility to the development of active disease following infection with M. tuberculosis. Furthermore, tuberculosis is often an early complication of HIV infection which precedes marked declines in CD4+ T-cell counts. In contrast to studies of other intracellular pathogens, in vitro addition of activating cytokines does not mediate significant reduction in the intracellular growth of M. tuberculosis. Utilizing a method of quantitative infection of human mononuclear phagocytes with virulent M. tuberculosis in which the interactions of lymphocytes with these infected cells can be characterized, preliminary studies indicate that addition of lymphocytes to cultures of M. tuberculosis-infected monocytes is more effective at limiting intracellular growth than is transfer of the supernatants of those cultures. It is hypothesized that cell-to-cell contact involving the interactions of specific cell surface molecules is necessary to maximally activate human mononuclear phagocytes to contain intracellular growth of M. tuberculosis. This hypothesis will be addressed in the following Specific Aims: 1) To determine the contact-dependent mechanisms by which antigen-specific CD4+ T-cells activate bactericidal functions of M. tuberculosis-infected mononuclear phagocytes; 2) To determine whether maximal CD4+ T cell-mediated activation of M. tuberculosis-infected mononuclear phagocytes requires sequential or interactive effects of cell contact and cytokine production; and 3) To determine whether CD8+ T-cells, gammadelta T-cells, and NK cells mediate contact-dependent activation of M. tuberculosis-infected mononuclear phagocytes, to compare the mechanisms used by these effector populations to those of CD4+ T cells, and to determine the role of Fas/FasL-mediated cytotoxic effector mechanisms on killing of M. tuberculosis within human mononuclear phagocytes.