MOLECULAR REGULATION OF MACROPHAGE CYTOCIDAL ACTIVITY

巨噬细胞杀细胞活性的分子调控

• 批准号: 3184940
• 负责人: ROBERT DAVID SCHREIBER
• 金额: $ 20.73万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-02-01 至 1989-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3184940
• 关键词: T lymphocyte; affinity chromatography; bactericidal immunity; cell cell interaction; cell mediated cytotoxicity; cellular immunity; complement; complement receptor; electron microscopy; enzyme inhibitors; enzyme mechanism; gel electrophoresis; human subject; hybridomas; immunoglobulins; ion exchange chromatography; laboratory mouse; laboratory rabbit; laboratory rat; leukocyte activation /transformation; luminescence; macrophage; membrane structure; migration inhibition factor; molecular sieving; neoplasm /cancer immunology; phagocytes; phagocytosis; protein biosynthesis; radiotracer; scintillation counter; tissue /cell culture

The ability of macrophages to destroy foreign cells such as bacteria and neoplastic cells forms the basis of an important mechanism of host defense. Although macrophage cytocidal activity appears to be a composite of three reactions involving activation, recognition, and target cell killing, detailed information of the mechanisms involved in these processes has remained scarce. This research seeks to elucidate the molecular events that lead to macrophage activation and to determine the effect of activation on macrophage recognition reactions and effector cell function. In the past, we placed particular emphasis on the purification and characterization of the soluble T-lymphocyte product, denoted macrophage activating factor (MAF), which is responsible for inducing macrophage cytocidal activity. On the basis of a variety of biosynthetic, physiochemical, and immunochemical criteria, we have found that the MAF activity produced by a murine T-cell hybridoma is totally attributable to gamma interferon (IFN-gamma). During the past year, we characterized a specific cell surface receptor for IFN-gamma that regulates macrophage activation. We also produced monoclonal antibodies to human and murine IFN-gamma and used these reagents to demonstrate the presence of distinct functional domains on IFN-gamma that induce different cellular activities. These antibodies have also been used to show that IFN-gamma is the major MAF made by normal T lymphocytes. Because of the recent reports that certain complement proteins can mimic specific lymphokines and influence activation of mononuclear phagocytes, the role of complement in the induction of macrophage cytocidal activity also will be examined. The membrane structures on macrophages that recognize target cells will be characterized. Phagocyte complement receptors also will be defined. A detailed analysis will be performed to quantitate the effects of activation on the function of these two types of cellular recognition structures. The results of these studies should provide additional insights into the molecular basis of macrophage function and thus enhance our understanding of the host defense system. (HF)

巨噬细胞破坏外来细胞如细菌和 肿瘤细胞形成的基础上，一个重要的机制，主机 防御 虽然巨噬细胞的杀细胞活性似乎是一种复合物， 三个反应，包括激活，识别和靶细胞 杀死，这些过程中所涉及的机制的详细信息 一直很稀少这项研究试图阐明分子事件 导致巨噬细胞活化，并确定 激活巨噬细胞识别反应和效应细胞功能。 过去，我们特别强调净化， 可溶性T淋巴细胞产物（表示为巨噬细胞）的表征 活化因子（MAF），其负责诱导巨噬细胞 杀细胞活性。 在多种生物合成的基础上， 根据生理化学和免疫化学标准，我们发现MAF 由鼠T细胞杂交瘤产生的活性完全归因于 γ干扰素（IFN-γ）。 在过去的一年里，我们描绘了一个 调节巨噬细胞的IFN-γ特异性细胞表面受体 activation. 我们还生产了抗人和鼠的单克隆抗体 IFN-γ和使用这些试剂来证明存在不同的 IFN-γ上的功能结构域诱导不同的细胞活性。 这些抗体也被用来表明IFN-γ是主要的 由正常T淋巴细胞产生的MAF。 由于最近有报道称， 某些补体蛋白可以模拟特定的淋巴因子， 单核吞噬细胞的激活，补体在 还将检测巨噬细胞杀细胞活性的诱导。 的 巨噬细胞上识别靶细胞的膜结构将被 表征了 还将定义吞噬细胞补体受体。 一 将进行详细的分析，以量化激活的影响 这两种细胞识别结构的功能。 的 这些研究的结果应该提供更多的见解， 巨噬细胞功能的分子基础，从而提高我们的理解 宿主防御系统 （HF）