CONTACT MEDIATED HOST RESISTANCE TO M TUBERCULOSIS

描述 结核病仍然是一个巨大的国际健康问题， 由于目前世界上有三分之一的人口感染了 病原体结核分枝杆菌细胞介导的免疫， 涉及致敏淋巴细胞与M. 结核病感染的单核吞噬细胞，可以容纳生物体， 结果发现大多数健康的人 感染后不会发展为活动性结核病。 艾滋病毒阳性者对艾滋病的易感性大大增加， 感染M.结核 此外，结核病往往是艾滋病毒感染的早期并发症 这是在CD 4 + T细胞计数显著下降之前。相比 其他细胞内病原体的研究，体外添加活化 细胞因子不介导细胞内生长的显著减少 分枝结核利用定量感染人的方法， 单核吞噬细胞与毒力M.肺结核，其中 可以表征淋巴细胞与这些感染细胞的相互作用， 初步研究表明，淋巴细胞加入M. 结核感染的单核细胞更有效地限制细胞内 比转移那些培养物的上清液更容易生长。是 假设细胞与细胞的接触， 特异性细胞表面分子是最大限度地激活人 单核吞噬细胞含有M.结核 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CD 4 + T细胞激活M.结核病感染者 单核吞噬细胞; 2）确定最大CD 4 + T细胞介导的 激活M。结核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相互作用; 和3）确定CD 8 + T细胞、γ δ T细胞和NK细胞是否 介导M的接触依赖性激活。结核感染单核细胞 吞噬细胞，比较这些效应群体使用的机制， 这些CD 4 + T细胞，并确定Fas/FasL介导的作用， 细胞毒效应机制的杀伤M.人体内结核病 单核吞噬细胞

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.