IN VITRO INDUCTION OF NK CYTOTOXICITY

NK 细胞毒性的体外诱导

• 批准号: 3172120
• 负责人: SIDNEY H GOLUB
• 金额: $ 16.76万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-02-12 至 1992-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3172120
• 关键词: T lymphocyte; cell cell interaction; cell population study; flow cytometry; human subject; immunoregulation; interleukin 2; leukocyte activation /transformation; monoclonal antibody; neoplasm /cancer immunology; suppressor T lymphocyte; tissue /cell culture; transferrin receptor

Lymphocytes can be induced to mediate cytotoxic reactions against a variety of target cells by in vitro manipulations. These reactions can be against either NK-sensitive target cells ("NK-like" or "anomalous" killing) or against NK-resistant targets ("lymphokine activated killing"). Cytotoxic reactivity can be induced with various stimuli including mixed lymphocyte culture or interleukin-2 (IL-2). These types of cytotoxicity bear a number of similarities with natural killer (NK) cell mediated cytotoxicity, although some features such as the spectrum of target cells killed are quite different. We propose to investigate the similarities between these types of cellular cytotoxicity basing our studies on the hypothesis that LAK and NK are of the same lineage, are regulated similarly, and recognize the same target structures. The ideal means to study the development of these effector cells would allow for the induction of cytotoxicity from non-cytotoxic precursors. We have developed two such precursor systems; the induction of cytotoxicity with IL-2 from naturally NK-inactive human thymocytes and IL-2 stimulation of peripheral blood lymphocytes depleted of NK cells with the toxic lysosomotropic drug L-leucine methyl ester. The phenotype of cells capable of developing cytotoxic reactivity, the sequence of signals that must be delivered to these cells to develop cytotoxic function, and the specificity of the induced cytotoxicity will be studied. The effects of adherent cells and adherent cell products on the in vitro development of cytotoxicity will be studied. We have demonstrated the existance of suppressor cells for NK effector function and for the acquisition of the IL-2 and transferrin receptors. These cells will be characterized and their mode of action determined. The specificity of LAK and NK cells will be compared by immunoselection of target cells with LAK or NK effector cells and comparing the sensitivity of the selected targets to these effector systems. By examining the similarities and differences between LAK and NK at the precursor, regulatory, and effector levels we expect to be able to determine the functional relationship between these cell types.

淋巴细胞可以被诱导来介导针对不同物种的细胞毒反应 通过体外操作获得靶细胞。这些反应可能会对 NK敏感的靶细胞(“NK样”或“异常”杀伤)或 针对NK耐药靶点(“淋巴因子激活的杀伤”)。细胞毒性 包括混合淋巴细胞在内的各种刺激都可以诱导反应性。 培养或白介素2(IL-2)。这些类型的细胞毒性具有许多 与自然杀伤(NK)细胞介导的细胞毒性相似， 尽管一些特征，如被杀死的目标细胞的光谱 完全不同。我们建议调查它们之间的相似之处 细胞细胞毒性的类型我们的研究基于这样的假设 LAK和NK具有相同的血统，受相似的调控，并识别 相同的目标结构。研究……发展的理想手段 这些效应细胞将允许从 不含细胞毒性的前体。我们已经开发了两个这样的前兆系统； IL-2对自然杀伤细胞无活性的人的细胞毒作用 胸腺细胞和IL-2对耗竭的外周血淋巴细胞的刺激 NK细胞用毒性溶酶体药物L-亮氨酸甲酯。这个 能够产生细胞毒性反应的细胞的表型，序列 必须传递给这些细胞的信号才能产生细胞毒作用 功能，以及诱导的细胞毒性的特异性将被研究。 贴壁细胞及贴壁细胞产物对体外培养细胞的影响 细胞毒性的发展将被研究。我们已经演示了 抑制细胞的存在对NK效应功能和对 IL-2和转铁蛋白受体的获得。这些细胞将是 确定了他们的特点和行动模式。LAK的特异性 通过免疫选择靶细胞与LAK细胞比较NK细胞 或NK效应细胞，并比较所选靶点的敏感性 这些效应器系统。通过考察它们的相似性和差异性 在LAK和NK的前体、调节和效应水平上，我们 期望能够确定它们之间的功能关系 单元类型。