Lotzová E, Savary C A, Herberman R B
J Immunol. 1987 Apr 15;138(8):2718-27.
Natural killer (NK) cells have been implicated in defense against malignancies, especially leukemia. Because patients with leukemia and preleukemic disorders manifest low NK activity, it is possible that NK cell impairment may contribute to leukemogenesis. In view of this possibility, it was important to characterize the NK cell defect of leukemic patients and to design new approaches for its correction. Analysis of the mechanism of NK cell defect demonstrated that NK cells of leukemic patients were impaired in their tumor-binding and lytic activity and did not display ability to recycle or to produce cytotoxic factor. However, deficient NK activity could be corrected by culture of peripheral blood effector cells with IL 2. IL 2-activated NK cells manifested restoration of all measured parameters of the cytotoxic mechanism, as exemplified by normalized tumor-binding and lytic activity, as well as the rate of lysis and ability to recycle. Importantly, such in vitro stimulated cytotoxic cells displayed reactivity against fresh leukemic cells of autologous as well as allogeneic origin. Another interesting observation from these studies was that the NK activity was also induced in the leukemic bone marrow, a tissue with a very low frequency of cytotoxic NK cells. It is important to note that cultured NK cells did not represent a stationary cell population, but proliferated in vitro quite actively (doubling time 3 to 6 days) for at least 5 wk. Characterization of the in vitro generated cytotoxic cells indicated that these cells displayed large granular lymphocyte morphology and CD16 and Leu-19 cell surface phenotype. Our data demonstrate that the NK cell defect of leukemic patients is not a permanent phenomenon, but can be reversed in culture with IL 2, and that fully cytotoxic NK cells can be maintained and expanded in vitro. Thus, it is reasonable to suggest that adoptive transfer of autologous NK cells to the patients may represent a promising new therapy for treatment of leukemia.
自然杀伤（NK）细胞在抵御恶性肿瘤尤其是白血病方面发挥着作用。由于白血病患者和白血病前期患者的NK活性较低，NK细胞功能受损可能参与白血病的发生。鉴于这种可能性，明确白血病患者NK细胞缺陷的特征并设计纠正该缺陷的新方法具有重要意义。对NK细胞缺陷机制的分析表明，白血病患者的NK细胞在肿瘤结合和裂解活性方面存在缺陷，且不具备再循环或产生细胞毒性因子的能力。然而，通过用白细胞介素2（IL-2）培养外周血效应细胞，可以纠正NK活性的缺陷。IL-2激活的NK细胞表现出细胞毒性机制所有测量参数的恢复，如正常化的肿瘤结合和裂解活性、裂解速率以及再循环能力。重要的是，这种体外刺激的细胞毒性细胞对自体和异体来源的新鲜白血病细胞均有反应。这些研究的另一个有趣发现是，在白血病骨髓中也诱导出了NK活性，而该组织中细胞毒性NK细胞的频率很低。需要注意的是，培养的NK细胞并非静止的细胞群体，而是在体外相当活跃地增殖（倍增时间为3至6天），至少持续5周。对体外产生的细胞毒性细胞的特征分析表明，这些细胞呈现大颗粒淋巴细胞形态以及CD16和Leu-19细胞表面表型。我们的数据表明，白血病患者的NK细胞缺陷并非永久性现象，而是可以在体外通过IL-2培养得到逆转，并且完全具有细胞毒性的NK细胞能够在体外维持和扩增。因此，合理的推测是，将自体NK细胞过继转移给患者可能是一种有前景的白血病新疗法。
