BIOLOGY OF CYTOKINE INDUCED KILLER CELLS

细胞因子诱导的杀伤细胞的生物学

• 批准号: 2112047
• 负责人: PEGGY P LU
• 金额: $ 8.1万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2112047
• 关键词: CD antigens; CD3 molecule; SCID mouse; T lymphocyte; acute lymphocytic leukemia; adeno associated virus group; antineoplastics; cell cycle; cell mediated cytotoxicity; cell population study; clone cells; colony stimulating factor; cytokine; disease /disorder model; flow cytometry; genetic transduction; human tissue; interleukin 2; killer cells; monoclonal antibody; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; passive immunization; phenotype; tissue /cell culture

The use of populations of cells with antitumor cell activity is an attractive alternative to standard chemotherapy for patients with cancer. Previously, we have reported a novel protocol for the generation of highly efficient cytotoxic effector cells by culturing PBLs in the presence of IFN-gamma on day 1, and IL-2, mAB-CD3 and IL-1 on the following day. We have termed these cultures cytokine-induced killer (CIK) cells, inasmuch as the phenotype of the cells with the greatest cytotoxic activity expresses both the T cell marker CD3 and the NK cell marker CD56. CD3+CD56+ cells are rare (1 about 5%) in uncultured PBLs, yet have been demonstrated to have MHC-unrestricted cytotoxicity. Recently, we have reported that under our culture conditions, the CD3+CD56+ cells expand nearly 1000-fold, of which the majority are derived from CD3_CD56- T cells, and not from CD3- CD56+ NK cells. The CIK cells have more potent antitumor activity as compared to lymphokine-activated killer cells in mice with severe combined immunodeficiency (SCID) and are more easily accessible than tumor infiltrating lymphocytes. In this proposal we will optimize the expansion and cytotoxicity of CD3+CD56+ cells (CIK effectors). We will evaluate whether growth factor and cytoxan-mobilized peripheral blood contains a larger number of precursor cells which are capable of expansion into CD3+CD56+ killer cells than steady state peripheral blood. We will investigate and characterize the functional properties of expanded CD3+CD56+ cells and their target cell specificity at the clonal level. Finally, we will utilize SCID mice as model to study in vivo antitumor activity of CIK cells under several conditions. We believe that by further study of the major effector cells in CIK culture, namely CD3+CD56+ cells, we will not only gain fundamental biological insights but also develop new treatment approaches for patients with cancer.

使用抗肿瘤细胞活性的细胞种群是一种 癌症患者标准化疗的有吸引力的替代品。 以前，我们已经报告了一种新颖的方案，用于生成高度 有效的细胞毒性效应细胞通过在存在的情况下培养PBL IFN-gamma在第1天，第二天IL-2，MAB-CD3和IL-1。 我们 已经称这些培养物是细胞因子诱导的杀手（CIK）细胞， 具有最大细胞毒性活性的细胞表型表达 T细胞标记CD3和NK细胞标记CD56均两者均。 CD3+ CD56+细胞 在未培养的PBL中很少见（约1％），但已证明 具有MHC无限制的细胞毒性。 最近，我们报告了 我们的培养条件，CD3+ CD56+细胞膨胀了近1000倍， 大多数是从CD3_CD56-T细胞得出的，而不是来自CD3- CD56+ NK细胞。 CIK细胞具有更有效的抗肿瘤活性 与严重合并的小鼠中的淋巴因子激活的杀伤细胞相比 免疫缺陷（SCID），比肿瘤更容易获得 浸润淋巴细胞。 在此提案中，我们将优化扩展 CD3+ CD56+细胞（CIK效应子）的细胞毒性。 我们将评估 生长因子和细胞分学动物的外周血是否包含 能够扩展到 CD3+ CD56+杀伤细胞比稳态外周血细胞。 我们将 调查并表征扩展的功能特性 CD3+ CD56+细胞及其靶细胞在克隆水平上的特异性。 最后，我们将利用SCID小鼠作为模型来研究体内抗肿瘤 CIK细胞在几种条件下的活性。 我们相信进一步 研究CIK培养的主要效应细胞，即CD3+ CD56+细胞， 我们不仅会获得基本的生物学见解，而且还会发展新的 癌症患者的治疗方法。