Baldwin G C, Chung G Y, Kaslander C, Esmail T, Reisfeld R A, Golde D W
Department of Medicine, UCLA School of Medicine 90024-1678.
Br J Haematol. 1993 Apr;83(4):545-53. doi: 10.1111/j.1365-2141.1993.tb04689.x.
We conducted experiments to determine the optimal conditions for colony-stimulating factor-enhanced neutrophil- and mononuclear phagocyte-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) using monoclonal antibodies to disialogangliosides expressed on neuroectodermal tumour target cells. Neutrophil ADCC was most effective at effector:target ratios of 100:1, with maximal cytotoxic responses to melanoma target cells generated by 3 h. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) were the most potent stimulators of neutrophil ADCC, and enhanced ADCC activity was inhibited in the presence of antibody to Fc receptor type II (FcRII). GM-CSF and macrophage colony-stimulating factor (M-CSF) treatment of freshly isolated monocytes inhibited antibody-independent cytotoxicity but enhanced antibody-dependent responses. After 3 d in culture with CSF, 3-10-fold enhancement of ADCC against melanoma target cells was observed at effector:target cell ratios of 10:1. Greatest stimulation of macrophage ADCC was obtained when GM-CSF, M-CSF or interleukin 3 (IL-3) were used in conjunction with a secondary stimulus. Although gamma interferon (gamma-IFN) did not augment the cytotoxic capability of GM-CSF- and IL-3-stimulated macrophages, prominent cytotoxic enhancement was seen when M-CSF-stimulated macrophages were exposed to gamma-IFN. A chimaeric mouse/human monoclonal antibody was found to be equivalent in activity to the murine antibody in neutrophil ADCC; however, in macrophage ADCC assays with submaximal effector cell stimulation, the chimaeric antibody was associated with a two-fold greater response. These studies indicate that under specific conditions, CSFs capable of increasing the number and functional activity of mature myeloid effector cells enhance antibody-dependent cytotoxicity to neuroectodermal tumour target cells.
我们进行了实验，以确定使用针对神经外胚层肿瘤靶细胞上表达的二唾液酸神经节苷脂的单克隆抗体，集落刺激因子增强中性粒细胞和单核吞噬细胞介导的抗体依赖细胞介导的细胞毒性（ADCC）的最佳条件。中性粒细胞ADCC在效应细胞与靶细胞比例为100:1时最有效，对黑色素瘤靶细胞的最大细胞毒性反应在3小时时产生。粒细胞-巨噬细胞集落刺激因子（GM-CSF）和粒细胞集落刺激因子（G-CSF）是中性粒细胞ADCC最有效的刺激剂，在存在抗II型Fc受体（FcRII）抗体的情况下，增强的ADCC活性受到抑制。GM-CSF和巨噬细胞集落刺激因子（M-CSF）对新鲜分离的单核细胞的处理抑制了非抗体依赖性细胞毒性，但增强了抗体依赖性反应。在用CSF培养3天后，在效应细胞与靶细胞比例为10:1时，观察到对黑色素瘤靶细胞的ADCC增强了3至10倍。当GM-CSF、M-CSF或白细胞介素3（IL-3）与二次刺激联合使用时，获得了对巨噬细胞ADCC的最大刺激。虽然γ干扰素（γ-IFN）没有增强GM-CSF和IL-3刺激的巨噬细胞的细胞毒性能力，但当M-CSF刺激的巨噬细胞暴露于γ-IFN时，观察到明显的细胞毒性增强。发现一种嵌合小鼠/人单克隆抗体在中性粒细胞ADCC中的活性与鼠源抗体相当；然而，在效应细胞刺激亚最大的巨噬细胞ADCC试验中，嵌合抗体的反应性高出两倍。这些研究表明，在特定条件下，能够增加成熟髓样效应细胞数量和功能活性的CSF可增强对神经外胚层肿瘤靶细胞的抗体依赖性细胞毒性。
