OPIATE MODULATION OF PULMONARY INFECTION

描述：(申请人摘要) 在全球范围内，结核病是由传染性疾病引起的主要死亡原因。 疾病。当感染从肺部扩散到中枢神经时 在中枢神经系统(CNS)中，未经治疗的结核病死亡率接近100%。医疗 损害细胞免疫的条件，包括艾滋病毒感染， 促进播散性结核病的发展，而免疫接种 牛分枝杆菌卡介苗预防传播 中枢神经系统。最近的研究表明，对结核病的免疫是由T细胞介导的 抑制结核杆菌生长的淋巴细胞亚群 在组织内的巨噬细胞。因为吗啡对细胞介导性的影响 免疫力，阿片类药物滥用被怀疑增加了易感性 为了结核病。然而，检验吗啡是否会促进 引起结核的任何一种分枝杆菌的致病性。 结核病或牛分枝杆菌)缺乏。需要检验的中心假说 在这项研究中提出的是吗啡促进了脑出血的免疫病理机制。 播散性牛分枝杆菌感染。为了检验这一假说，在体外和 体内实验将使用猪的播散性模型进行 结核病。其具体目的是：(1)表征吗啡对小鼠的影响。 体外对牛分枝杆菌感染小胶质细胞和单核细胞的影响；(2)测定 研究了非免疫猪对吗啡依赖对M。 Bovis在体内的小胶质细胞中的表达，并与这些组织病理学相关 临床表现与中枢神经系统感染的关系；(3) 吗啡体外抗结核分枝杆菌的作用T淋巴细胞的牛黄活性 从卡介苗免疫的猪中获得的亚群；和(4)决定了 吗啡在卡介苗免疫猪中对中枢神经系统结核疫苗的保护作用。 小胶质细胞和单核细胞的原代培养将从 新生的猪。除了在体外研究吗啡对大鼠脑内神经递质的影响外 牛分枝杆菌与这些细胞群的相互作用及其影响 吗啡对小鼠T淋巴细胞亚群抗分枝杆菌活性的影响 免疫的动物将被确定。一种新的活体猪模型 将使用播散性牛分枝杆菌感染的。我们假设吗啡 给未免疫的猪注射会促进中枢神经系统结核病的发展， 而给卡介苗免疫的猪注射吗啡将与 失去疫苗对中枢神经系统结核病的保护作用。这些研究将会， 首次提供与临床相关的实验证据 令人担忧的是，阿片类药物滥用助长了结核病的发病。

DESCRIPTION: (Applicant's Abstract) Globally, tuberculosis (TB) is the leading cause of death from infectious disease. When infection disseminates from the lungs to the central nervous system (CNS), the mortality of TB, when untreated, approaches 100%. Medical conditions that impair cell-mediated immunity, including HIV infection, foster the development of disseminated TB, whereas immunization with Mycobacterium bovis BCG vaccine confers protection against dissemination to the CNS. Recent studies indicate that immunity against TB is mediated by T lymphocyte subpopulations, which inhibit the growth of the tubercle bacillus within tissue macrophages. Because of morphine's effects on cell-mediated immunity, opiate abuse has been suspected of increasing the susceptibility to TB. However, experimental studies examining whether morphine promotes the pathogenicity of either of the mycobacterial species that cause TB (M. tuberculosis or M. bovis) are lacking. The central hypothesis to be tested in the research proposed is that morphine promotes the immunopathogenesis of disseminated M. bovis infection. To test the hypothesis, both in vitro and in vivo experiments will be conducted using a swine model of disseminated TB. The specific aims are to: (1) characterize the effect of morphine in vitro on M. bovis infection of microglial cells and monocytes; (2) determine the effect of morphine dependence of non-immunized swine on the growth of M. bovis in microglial cells in vivo, and correlate these histopathologic findings with the clinical course of CNS infection; (3) characterize the effect of morphine in vitro on the anti-M. bovis activity of T lymphocyte subsets obtained from BCG-immunized swine; and (4) determine the effect of morphine in BCG-immunized swine on vaccine protection against CNS TB. Primary cultures of microglial cells and monocytes will be obtained from neonatal pigs. In addition to studying the effects of morphine in vitro on the interaction between M. bovis and these cell populations, the influence of morphine on the anti-mycobacterial activity of T lymphocyte subsets from immunized animals will be determined. A newly developed in vivo swine model of disseminated M. bovis infection will be used. We postulate that morphine administered to non-immunized swine will promote the development of CNS TB, whereas morphine administered to BCG-immunized swine will be associated with loss of the vaccine's protective effect against CNS TB. These studies will, for the first time, provide experimental evidence relevant to the clinical concern that opiate abuse fosters the pathogenesis of TB.