Temporal, quantitative, and functional characteristics of single-KIR-positive alloreactive natural killer cell recovery account for impaired graft-versus-leukemia activity after haploidentical hematopoietic stem cell transplantation
Temporal, quantitative, and functional characteristics of single-KIR-positive alloreactive natural killer cell recovery account for impaired graft-versus-leukemia activity after haploidentical hematopoietic stem cell transplantation
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DOI：
10.1182/blood-2007-07-103325
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发表时间：
2008-10-15
期刊：
影响因子：
20.3
通讯作者：
Fleischhauer, Katharina
中科院分区：
文献类型：
--
作者：
Vago, Luca;Forno, Barbara;Fleischhauer, Katharina
在这项研究中，我们的特点是重建的自然杀伤（NK）细胞库后，单倍体相合的CD 34（+）选择造血干细胞移植（HSCT）的高危血液系统恶性肿瘤。分析集中在同种异体反应性单KIR + NK细胞，据报道，这是有效的抗白血病效应。HSCT后1个月，CD 56（亮）/CD 56（暗）NK细胞亚群显示倒置比例和表型特征。CD 25和CD 117在CD 56（亮）上的下调，以及NKG 2A和CD 62 L在CD 56（暗）上的上调，表明体内连续的CD 56（亮）-至-CD 56（暗）NK细胞成熟。因此，这些成熟中间体对白血病母细胞的功能潜力受损。成熟受体库重建至少需要3个月。重要的是，在这个时间点，据称同种异体反应性的单KIR + NK细胞尚未完全发挥功能。这些细胞的频率是高度可变的，独立于预测的NK同种异体反应性，和低于1%的NK细胞在3 6同种异体反应性患者研究。与这些观察结果一致，在56例患者的总队列中未观察到预测NK同种异体反应性的临床获益。我们的研究结果解开了动力学，和限制，从纯化的单倍体相合造血干细胞在体内的NK细胞分化，并建议，NK细胞抗白血病的潜力，可以最好地利用输注的成熟的单KIR + NK细胞从同种异体反应供体选择。
In this study, we have characterized reconstitution of the natural killer (NK) cell repertoire after haploidentical CD34(+) selected hematopoietic stem cell transplantation (HSCT) for high-risk hematologic malignancies. Analysis focused on alloreactive single-KIR+ NK cells, which reportedly are potent antileukemic effectors. One month after HSCT, CD56(bright)/CD56(dim) NK-cell subsets showed inverted ratio and phenotypic features. CD25 and CD117 down-regulation on CD56(bright), and NKG2A and CD62L up-regulation on CD56(dim), suggest sequential CD56(bright)-to-CD56(dim) NK-cell maturation in vivo. Consistently, the functional potential of these maturation intermediates against leukemic blasts was impaired. Mature receptor repertoire reconstitution took at least 3 months. Importantly, at this time point, supposedly alloreactive, single-KIR+ NK cells were not yet fully functional. Frequency of these cells was highly variable, independently from predicted NK alloreactivity, and below 1% of NK cells in 3 of 6 alloreactive patients studied. In line with these observations, no clinical benefit of predicted NK alloreactivity was observed in the total cohort of 56 patients. Our findings unravel the kinetics, and limits, of NK-cell differentiation from purified haploidentical hematopoietic stem cells in vivo, and suggest that NK-cell antileukemic potential could be best exploited by infusion of mature single-KIR+ NK cells selected from an alloreactive donor.