IN VITRO INDUCTION OF NK CYTOTOXICITY

NK 细胞毒性的体外诱导

• 批准号: 3172121
• 负责人: SIDNEY H GOLUB
• 金额: $ 17.05万
• 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/3172121
• 关键词: T lymphocyte; cell cell interaction; cell population study; flow cytometry; human subject; immunoregulation; interleukin 2; leukocyte activation /transformation; monoclonal antibody; natural killer cells; 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.

淋巴细胞可被诱导介导针对多种 靶细胞的体外操作。 这些反应可能会对 NK敏感性靶细胞（“NK样”或“异常”杀伤）或 针对NK抗性靶点（“淋巴因子激活的杀伤”）。 细胞毒性 反应性可以用各种刺激物诱导，包括混合淋巴细胞 培养物或白细胞介素-2（IL-2）。 这些类型的细胞毒性具有一些 与自然杀伤（NK）细胞介导的细胞毒性相似， 尽管某些特征如被杀死的靶细胞的谱 完全不同 我们建议调查这些之间的相似之处 细胞毒性的类型基于我们的研究假设， LAK和NK属于同一谱系，调节相似，并识别 相同的目标结构。 理想的手段来研究的发展 这些效应细胞将允许诱导细胞毒性， 非细胞毒性前体。 我们已经开发了两个这样的前体系统; IL-2对自然NK失活人细胞的细胞毒性诱导 胸腺细胞和IL-2刺激的外周血淋巴细胞消耗的 NK细胞与毒性溶酶体药物L-亮氨酸甲酯。 的 表型的细胞能够发展细胞毒性反应，序列 这些信号必须传递到这些细胞， 功能，并将研究诱导的细胞毒性的特异性。 贴壁细胞及贴壁细胞产物对体外培养的 将研究细胞毒性的发展。 我们已经展示了 存在抑制NK效应细胞功能和 获得IL-2和转铁蛋白受体。 这些细胞将 其特征在于，其作用方式被确定。 LAK细胞的特异性 通过LAK细胞对靶细胞的免疫选择性比较NK细胞 或NK效应细胞，并比较所选靶标的敏感性 to these effector效应systems系统. 通过研究它们之间的异同 LAK和NK在前体、调节和效应水平上的关系， 希望能够确定这些之间的功能关系 细胞类型。