ALVEOLAR MACROPHAGE FUNCTION DURING IMMUNOSUPPRESSION

免疫抑制期间的肺泡巨噬细胞功能

• 批准号: 3340356
• 负责人: JUDD E SHELLITO
• 金额: $ 13.89万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-08-01 至 1993-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3340356
• 关键词: Pneumocystis; T lymphocyte; aerosols; alveolar macrophages; arachidonate; cellular immunity; cytokine; cytotoxicity; diagnostic respiratory lavage; disease /disorder model; glucocorticoids; interleukin 1; laboratory rat; leukocyte activation /transformation; lung disorder; particle counter; pneumonia; radiation immunosuppression; receptor; respiratory function; surface antigens

The overall objective of this project is to define mechanisms for the regulation of alveolar macrophage function. The current study will investigate how immunosuppression influences the functions of alveolar macrophages and what effect this may have on host defense against opportunistic pulmonary infection. It is our hypothesis that immunosuppression decreases alveolar macrophage function and that this decreased function is important in the pathogenesis of opportunistic infection. The present proposal will test this hypothesis in the rat, using glucocorticoid treatment as a model of immunosuppression and Pneumocystis carinii pneumonia as a model of opportunistic infection. Specific Aim 1. To characterize the effects of experimentally- induced immunosuppression on alveolar macrophage function. Alveolar macrophages will be recovered from glucocorticoid- treated rats at serial intervals and examined for functions relevant to host defense against infection: cytotoxic function, expression of Ia determinants, elaboration of interleukin-1, and release of arachidonic acid metabolites. Glucocorticoid-treated rats will also be monitored for infection with Pneumocystis carinii, so that changes in the functions of alveolar macrophages can be correlated with the development of infection. Specific Aim 2. To examine whether functions of alveolar macrophages which are decreased during immunosuppression can be increased in vitro. Alveolar macrophages from glucocorticoid- treated rats will be cultured in vitro with recombinant interferon gamma and tumor necrosis factor alpha to see if specific functions can be increased in response to these cytokines. Specific Aim 3. To examine whether functions of alveolar macrophages which are decreased during immunosuppression can be increased in vivo. Based upon the results of experiments performed for Specific Aims 1 and 2, glucocorticoid-treated rats will be exposed to aerosolized cytokines at selected time points. The functions of lavaged alveolar macrophages will then be assayed to see if aerosolized cytokines can increase the function of these cells in vivo. Specific Aim 4. To examine whether increasing alveolar macrophage function in vivo can prevent or ameliorate opportunistic infection of the lungs. Based upon the results of experiments performed for Specific Aim 3, glucocorticoid-treated rats will be exposed to aerosolized cytokine(s) and monitored for infection with Pneumocystis carinii, to see if increasing alveolar macrophage function in vivo will influence the natural history of this infection. The results of these experiments will provide new information as to how immunosuppression affects specific alveolar macrophage functions and how this influences host defense against Pneumocystis carinii. The ability to increase alveolar macrophage function by aerosol delivery of cytokines may warrant extension of this work to the study of humans with immunosuppression and opportunistic pulmonary infections.

该项目的总体目标是定义机制 肺泡巨噬细胞功能的调节。 目前的 研究将调查免疫抑制如何影响 肺泡巨噬细胞的功能及其可能产生的影响 宿主对机会性肺部感染的防御。 这是 我们的假设是免疫抑制会减少肺泡 巨噬细胞功能，这种功能下降是 在机会性感染的发病机制中具有重要意义。 这 目前的提议将在大鼠中测试这一假设，使用 糖皮质激素治疗作为免疫抑制模型 卡氏肺孢子虫肺炎作为机会性肺炎模型 感染。 具体目标 1. 表征实验效果- 诱导肺泡巨噬细胞功能的免疫抑制。 肺泡巨噬细胞将从糖皮质激素中回收- 连续间隔治疗大鼠并检查其功能 与宿主防御感染相关：细胞毒功能， Ia 决定簇的表达、白介素-1 的详细阐述，以及 花生四烯酸代谢物的释放。 糖皮质激素治疗 还将监测大鼠的肺孢子虫感染情况 carinii，使肺泡巨噬细胞的功能发生变化 可能与感染的发生有关。 具体目的2.检查肺泡功能是否正常 免疫抑制期间巨噬细胞减少 体外增加。 来自糖皮质激素的肺泡巨噬细胞- 治疗后的大鼠将用重组干扰素进行体外培养 γ 和肿瘤坏死因子 α 看看是否有特异性 对这些细胞因子的反应可以增强功能。 具体目的 3. 检查肺泡功能是否正常 免疫抑制期间巨噬细胞减少 体内增加。 根据实验结果 针对具体目标 1 和 2、糖皮质激素治疗的大鼠进行 将在选定的时间点暴露于雾化的细胞因子。 灌洗后的肺泡巨噬细胞的功能将被 检测雾化细胞因子是否可以增强功能 这些细胞在体内。 具体目标 4. 检查肺泡是否增加 体内巨噬细胞功能可以预防或改善 肺部机会性感染。 根据结果 针对特定目标 3 进行的实验，经糖皮质激素处理 大鼠将暴露于雾化细胞因子并监测 卡氏肺囊虫感染，看肺泡是否增大 体内巨噬细胞的功能将影响自然史 这种感染。 这些实验的结果将提供新的信息： 免疫抑制如何影响特定的肺泡巨噬细胞 功能以及这如何影响宿主防御 卡氏肺孢子虫。 增加肺泡的能力 巨噬细胞通过气溶胶递送细胞因子发挥功能 保证将这项工作扩展到对人类的研究 免疫抑制和机会性肺部感染。