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.

使用具有抗肿瘤细胞活性的细胞群是一种 对于癌症患者来说，这是标准化疗的有吸引力的替代方案。 之前，我们报道了一种用于生成高度 通过在存在以下物质的情况下培养 PBL 来产生有效的细胞毒性效应细胞 第 1 天使用 IFN-gamma，第二天使用 IL-2、mAB-CD3 和 IL-1。 我们 将这些培养物称为细胞因子诱导的杀伤（CIK）细胞，因为 具有最大细胞毒活性的细胞的表型表达 T 细胞标记 CD3 和 NK 细胞标记 CD56。 CD3+CD56+细胞 在未培养的 PBL 中很少见（1 约 5%），但已被证明 具有 MHC 不受限制的细胞毒性。 近日，我们报道称，根据 在我们的培养条件下，CD3+CD56+细胞扩增了近1000倍， 其中大部分源自 CD3_CD56- T 细胞，而不是 CD3- CD56+ NK 细胞。 CIK 细胞具有更有效的抗肿瘤活性 与患有严重联合病症的小鼠中淋巴因子激活的杀伤细胞相比 免疫缺陷（SCID）并且比肿瘤更容易接触 浸润淋巴细胞。 在这个提案中我们将优化扩展 和 CD3+CD56+ 细胞（CIK 效应细胞）的细胞毒性。 我们将评估 生长因子和细胞毒素动员的外周血是否含有 大量的前体细胞能够扩展成 CD3+CD56+杀伤细胞高于稳态外周血。 我们将 研究并表征扩展的功能特性 CD3+CD56+ 细胞及其在克隆水平上的靶细胞特异性。 最后，我们将利用SCID小鼠作为模型来研究体内抗肿瘤作用 CIK细胞在多种条件下的活性。 我们相信，通过进一步 CIK培养物中主要效应细胞的研究，即CD3+CD56+细胞， 我们不仅将获得基本的生物学见解，而且还将开发新的 癌症患者的治疗方法。