Sconocchia Giuseppe, Lau Michelle, Provenzano Maurizio, Rezvani Katayoun, Wongsena Wachanan, Fujiwara Hiroshi, Hensel Nancy, Melenhorst Jos, Li Jonming, Ferrone Soldano, Barrett A John
Stem Cell Allotransplantation Section, Hematology Branch, National Heart Lung and Blood Institute, Department of Transfusion Medicine, Clinical Center, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Blood. 2005 Nov 15;106(10):3666-72. doi: 10.1182/blood-2005-02-0479. Epub 2005 Jul 26.
To study natural killer (NK) cell-mediated antileukemic activity in chronic myelogenous leukemia (CML), we investigated the ability of HLA-matched and mismatched CD56(+) cells to inhibit granulocyte macrophage-colony-forming unit (CFU-GM) formation by leukemic CD34(+) cells. In 14 HLA-identical donor-recipient pairs, donor CD56(+) cells inhibited CML CFU-GM comparably to effectors from 14 HLA-mismatched unrelated individuals (mean inhibition 42% +/- 9% vs 39.5% +/- 7% at a 10:1 effector-to-target (E/T) ratio), suggesting that killer inhibitory receptor (KIR) incompatibility was not essential for an antileukemic effect. Both CD56(+)CD3(-) (natural killer [NK]) and CD56(+)CD3(+)(NK-T) cells inhibited CFU-GM growth of CML but not normal CD34(+) cells. A mechanism for this leukemia-specific cytotoxicity was suggested by the abnormal overexpression of major histocompatibility class I chain-related gene A or gene B (MICA/B) on CML CD34 cells and their ability to bind the NK activation ligand NKG2D. However, in vivo, CML cells may avoid NK-cell-mediated immune destruction by immune escape, shedding MICA into the plasma, thereby down-regulating NKG2D on CML CD56(+) cells.
为研究慢性粒细胞白血病（CML）中自然杀伤（NK）细胞介导的抗白血病活性，我们调查了HLA匹配和不匹配的CD56(+)细胞抑制白血病CD34(+)细胞形成粒细胞巨噬细胞集落形成单位（CFU-GM）的能力。在14对HLA相同的供体-受体对中，供体CD56(+)细胞抑制CML CFU-GM的能力与14名HLA不匹配的无关个体的效应细胞相当（在效应细胞与靶细胞比例为10:1时，平均抑制率分别为42%±9%和39.5%±7%），这表明杀伤抑制受体（KIR）不相容对于抗白血病效应并非必不可少。CD56(+)CD3(-)（自然杀伤[NK]）细胞和CD56(+)CD3(+)（NK-T）细胞均抑制CML的CFU-GM生长，但不抑制正常CD34(+)细胞。CML CD34细胞上主要组织相容性复合体I类链相关基因A或基因B（MICA/B）异常过表达及其与NK激活配体NKG2D结合的能力提示了这种白血病特异性细胞毒性的机制。然而，在体内，CML细胞可能通过免疫逃逸避免NK细胞介导的免疫破坏，将MICA释放到血浆中，从而下调CML CD56(+)细胞上的NKG2D。
