OPIATE MODULATION OF PULMONARY INFECTION

描述：（申请人摘要） 在全球范围内，结核病（TB）是感染性疾病死亡的主要原因。 疾病 当感染从肺部扩散到中枢神经系统时 在中枢神经系统（CNS）中，结核病的死亡率在未经治疗时接近100%。 医疗 损害细胞介导的免疫力的病症，包括HIV感染， 促进传播性结核病的发展， 牛分枝杆菌BCG疫苗可防止传播至 CNS。 最近的研究表明，抗结核免疫是由T 淋巴细胞亚群，其抑制结核杆菌的生长 在组织巨噬细胞内。 由于吗啡对细胞介导的 免疫，阿片类药物滥用已被怀疑增加易感性 肺结核 然而，研究吗啡是否促进 引起TB的任一种分枝杆菌的致病性（M. 结核或M.牛（bovis）缺乏。 待检验的中心假设 在这项研究中提出的是，吗啡促进免疫发病机制， 散布型M.牛传染病 为了验证这一假设，在体外和 体内实验将使用猪播散性骨髓瘤模型进行 TB. 具体的目的是：（1）表征吗啡在 在M.牛感染的小胶质细胞和单核细胞;（2）确定 非免疫猪吗啡依赖对M. 牛在小胶质细胞在体内，并关联这些组织病理学 结果与CNS感染的临床过程;（3）表征 吗啡对小鼠抗M. 牛T淋巴细胞活性 从BCG免疫的猪获得的亚群;和（4）确定 卡介苗免疫猪吗啡对中枢神经系统结核病的疫苗保护作用。 小胶质细胞和单核细胞的原代培养物将从 新生猪 除了在体外研究吗啡对 M.牛和这些细胞群， 吗啡对人外周血T淋巴细胞亚群抗分枝杆菌活性的影响 将确定免疫动物。 一种新的活体猪模型 传播的M.将使用牛感染。 我们假设吗啡 施用给未免疫的猪将促进CNS TB的发展， 而给予BCG免疫猪的吗啡将与 疫苗对中枢神经系统结核病的保护作用丧失。 这些研究将， 首次提供与临床相关的实验证据， 人们担心阿片类药物滥用会促进结核病的发病。

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.