CELL BIOLOGY OF THE IMMUNE RESPONSE TO BACTERIA

对细菌免疫反应的细胞生物学

• 批准号: 3480604
• 负责人: PRISCILLA A CAMPBELL
• 金额: $ 13.97万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 1976
• 资助国家: 美国
• 起止时间: 1976-08-01 至 1991-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3480604
• 关键词: Listeria; T lymphocyte; bacterial antigens; bactericidal immunity; cell biology; cellular immunity; chemotaxis; flow cytometry; gel electrophoresis; humoral immunity; inflammation; interferons; interleukin 2; laboratory mouse; lymphokines; macrophage; macrophage activating factor; microorganism immunology; migration inhibition factor; monoclonal antibody; neutrophil; phagocytes; phagocytic dysfunction; phagocytosis

Over the past grant period, we have generated considerable data which implicate inflammatory phagocytes as an important component of resistance to infection by facultative intracellular bacteria. Using murine resistance to the facultative intracellular bacterium, Listeria monocytogenes, as a model system, we have shown that T cells which transfer resistance from immune mice to normal mice also transfer the ability to accumulate inflammatory macrophages and neutrophils in response to antigenic challenge. Inflammatory peritoneal neutrophils and macrophages are bactericidal; resident cells are not. Other studies show that the major defect in mice genetically-susceptible to listeria is in their ability to accumulate cells at the site of infection. Finally, macrophages can be selectively stimulated to express tumoricidal but not bactericidal activity, or bactericidal but not tumoricidal activity. Tumoricidal activity by activated macrophages can be dissociated from bactericidal activity. Based on these and other findings, we now wish to test the hypothesis that the major way in which T cells mediate resistance to facultative intracellular bacteria is by causing an influx of inflammatory phagocytes which are inherently bactericidal. It is possible they also enhance the ability of these cells to kill bacteria. To test this hypothesis, we will pursue four specific aims. First, we will clone listeria-reactive T cells and test them for production of biologically-active secretory products which contribute to resistance by enhancing recruitment of inflammatory responses. Second, we will determine whether genetically-susceptible mice have defects at the level of the T cell, the responding inflammatory phagocyte, or both. Third, we will determine whether gamma-interferon can stimulate macrophages to become bactericidal, and whether it can directly or indirectly enhance accumulation of inflammatory bactericidal phagocytes. Finally, we will continue to evaluate biologic properties of listeria components, with an emphasis on identifying and isolating the materials which cause inflammatory responses. It is expected that these studies will contribute to our understanding of how T cells mediate resistance to facultative intracellular bacteria, and perhaps to other microorganisms as well.

在过去的赠款期间，我们生成了大量数据，这些数据 牵连炎性吞噬细胞作为抵抗的重要组成部分 对兼性胞内细菌的感染。用小鼠 对兼性胞内细菌李斯特氏菌的抗性 单核细胞增多症，作为一个模型系统，我们已经证明了T细胞 免疫小鼠对正常小鼠的抵抗力也转移到 聚集炎性巨噬细胞和中性粒细胞以应对 抗原性挑战。炎性腹膜中性粒细胞和巨噬细胞 是杀菌的；驻留细胞不是。其他研究表明， 对李斯特菌遗传敏感的小鼠的主要缺陷是 在感染部位积聚细胞的能力。最后，巨噬细胞 可以选择性地刺激表达杀瘤但不杀菌 活性，或杀菌，但不杀瘤活性。杀瘤作用 激活的巨噬细胞的活性可以从杀菌中分离出来 活动。 基于这些和其他发现，我们现在希望检验这一假设 T细胞介导兼性耐药的主要途径 细胞内细菌是通过引起炎性吞噬细胞的涌入 它们天生就是杀菌剂。有可能他们还增强了 这些细胞杀死细菌的能力。为了检验这一假设，我们将 追求四个具体目标。首先，我们将克隆李斯特菌反应性T细胞 并测试它们以生产具有生物活性的分泌产品 它们通过增加炎症性细胞的招募而导致耐药性 回应。其次，我们将确定遗传易感的小鼠 在T细胞水平上有缺陷，相应的炎症 吞噬细胞或两者兼而有之。第三，我们将确定伽马干扰素是否可以 刺激巨噬细胞变得杀菌，它是否可以直接 或间接增加炎性杀菌剂的积聚 吞噬细胞。最后，我们将继续评估其生物学特性。 李斯特菌组分，重点是鉴定和分离 引起炎症反应的材料。预计这些 研究将有助于我们理解T细胞是如何调节 对兼性胞内细菌的抗性，或许对其他细菌的抗性 微生物也是如此。