Carbone Ennio, Neri Paola, Mesuraca Maria, Fulciniti Mariateresa T, Otsuki Takemi, Pende Daniela, Groh Veronika, Spies Thomas, Pollio Giuditta, Cosman David, Catalano Lucio, Tassone Pierfrancesco, Rotoli Bruno, Venuta Salvatore
Dipartimento di Medicina Sperimentale e Clinica G. Salvatore, Università di Catanzaro Magna Graecia, Catanzaro, Italy.
Blood. 2005 Jan 1;105(1):251-8. doi: 10.1182/blood-2004-04-1422. Epub 2004 Aug 24.
The role of natural killer (NK) cells in multiple myeloma is not fully understood. Here, NK susceptibility of myeloma cells derived from distinct disease stages was evaluated in relation to major histocompatibility complex (MHC) class I, MHC class I chain-related protein A (MICA), MHC class I chain-related protein B (MICB), and UL16 binding protein (ULBP) expression. MHC class I molecules were hardly detectable on bone marrow cells of early-stage myeloma, while late-stage pleural effusion-derived cell lines showed a strong MHC class I expression. Conversely, a high MICA level was found on bone marrow myeloma cells, while it was low or not measurable on pleural effusion myeloma cells. The reciprocal surface expression of these molecules on bone marrow- and pleural effusion-derived cell was confirmed at mRNA levels. While bone marrow-derived myeloma cells were readily recognized by NK cells, pleural effusion-derived lines were resistant. NK protection of pleural effusion cells was MHC class I dependent. Receptor blocking experiments demonstrated that natural cytotoxicity receptor (NCR) and NK receptor member D of the lectin-like receptor family (NKG2D) were the key NK activating receptors for bone marrow-derived myeloma cell recognition. In ex vivo experiments patient's autologous fresh NK cells recognized bone marrow-derived myeloma cells. Our data support the hypothesis that NK cell cytotoxicity could sculpture myeloma and represents an important immune effector mechanism in controlling its intramedullary stages.
自然杀伤（NK）细胞在多发性骨髓瘤中的作用尚未完全明确。在此，我们评估了源自不同疾病阶段的骨髓瘤细胞对NK细胞的敏感性，及其与主要组织相容性复合体（MHC）I类分子、MHC I类链相关蛋白A（MICA）、MHC I类链相关蛋白B（MICB）和UL16结合蛋白（ULBP）表达的关系。在早期骨髓瘤患者的骨髓细胞上几乎检测不到MHC I类分子，而晚期胸腔积液来源的细胞系则表现出较强的MHC I类分子表达。相反，在骨髓骨髓瘤细胞上发现高表达的MICA，而在胸腔积液骨髓瘤细胞上其表达水平较低或无法检测到。在mRNA水平上证实了这些分子在骨髓和胸腔积液来源细胞上的相互表面表达。虽然骨髓来源的骨髓瘤细胞很容易被NK细胞识别，但胸腔积液来源的细胞系具有抗性。NK细胞对胸腔积液细胞的保护作用依赖于MHC I类分子。受体阻断实验表明，自然细胞毒性受体（NCR）和凝集素样受体家族的NK受体成员D（NKG2D）是识别骨髓来源骨髓瘤细胞的关键NK激活受体。在体外实验中，患者的自体新鲜NK细胞能够识别骨髓来源的骨髓瘤细胞。我们的数据支持这样一种假说，即NK细胞的细胞毒性作用能够塑造骨髓瘤，并且是控制其髓内阶段的一种重要免疫效应机制。
