Miller J S, Prosper F, McCullar V
Department of Medicine, University of Minnesota, Minneapolis 55455, USA.
Blood. 1997 Oct 15;90(8):3098-105.
Granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cell (PBPC) collections are increasingly emerging as the graft of choice in many centers for autologous transplantation, and with increasing frequency for allogeneic transplantation. However, the role of myeloid cytokines in lymphoid function, lymphoid progenitors, and immune-mediated antitumor responses is not known. We studied PBPC collections from normal donors mobilized with G-CSF (10 microg/kg). CD56+/CD3- natural killer (NK) cells sorted from PBPC products exhibited a diminished ability to kill tumor targets, were less responsive in acquiring increased cytolysis with interleukin-2 (IL-2), and proliferated less than NK cells from normal unprimed peripheral blood. This abnormality was not explained by a change in phenotype of NK cells normally circulating in the blood after G-CSF administration. We could not demonstrate any direct suppressive effect on normal unprimed NK cell proliferation or cytotoxicity by culture with pharmacologic concentrations of G-CSF. We next evaluated the effects of G-CSF on CD34+ NK cell progenitors. CD34+/CD2+, CD34+/CD7+, and CD34+/CD10+ progenitors were markedly diminished in G-CSF-mobilized PBPC products. CD34+ cells cultured in limiting dilution assays showed a sixfold decrease in NK cell progenitors when derived from G-CSF-mobilized CD34+ PBPCs compared with CD34+ cells derived from unprimed marrow. The finding of decreased NK cell function, inhibited proliferation, and diminished cloning frequency after treatment with G-CSF could be mimicked in vitro by culture of primitive marrow progenitors (CD34+, lineage-negative, HLA-DR-) on stromal layers in the presence of exogenous G-CSF. The findings presented here show that G-CSF administration to normal donors decreases NK cell function and the relative frequency of NK cell progenitors within the CD34+ progenitor population. Overcoming this diminished lymphoid capacity may be important to facilitate early posttransplant immunotherapy. Our in vitro model will be used in future studies to determine the mechanism of the G-CSF-induced suppression of NK cell progenitors, which may occur early in the differentiation process.
粒细胞集落刺激因子（G-CSF）动员的外周血祖细胞（PBPC）采集越来越多地成为许多中心自体移植的首选移植物，并且在异基因移植中的应用频率也越来越高。然而，髓系细胞因子在淋巴细胞功能、淋巴祖细胞和免疫介导的抗肿瘤反应中的作用尚不清楚。我们研究了用G-CSF（10微克/千克）动员的正常供体的PBPC采集情况。从PBPC产品中分选出来的CD56+/CD3-自然杀伤（NK）细胞杀伤肿瘤靶标的能力减弱，在用白细胞介素-2（IL-2）增强细胞溶解作用时反应性较低，并且其增殖能力低于正常未致敏外周血中的NK细胞。这种异常不能用G-CSF给药后血液中正常循环的NK细胞表型变化来解释。我们未能证明用药理浓度的G-CSF培养对正常未致敏NK细胞的增殖或细胞毒性有任何直接抑制作用。接下来，我们评估了G-CSF对CD34+NK细胞祖细胞的影响。在G-CSF动员的PBPC产品中，CD34+/CD2+、CD34+/CD7+和CD34+/CD10+祖细胞明显减少。在有限稀释分析中培养的CD34+细胞显示，与从未致敏骨髓来源的CD34+细胞相比，来自G-CSF动员的CD34+PBPC的细胞中NK细胞祖细胞减少了六倍。在用G-CSF治疗后NK细胞功能降低、增殖受抑制和克隆频率降低的现象，在体外通过在存在外源性G-CSF的基质层上培养原始骨髓祖细胞（CD34+；谱系阴性；HLA-DR-）可以模拟出来。此处呈现的研究结果表明，对正常供体给予G-CSF会降低NK细胞功能以及CD34+祖细胞群体中NK细胞祖细胞的相对频率。克服这种淋巴细胞能力的降低对于促进移植后早期免疫治疗可能很重要。我们的体外模型将用于未来的研究，以确定G-CSF诱导的NK细胞祖细胞抑制的机制，这种抑制可能发生在分化过程的早期。
