Mariani S, Muraro M, Pantaleoni F, Fiore F, Nuschak B, Peola S, Foglietta M, Palumbo A, Coscia M, Castella B, Bruno B, Bertieri R, Boano L, Boccadoro M, Massaia M
Laboratorio di Ematologia Oncologica, Centro di Ricerca in Medicina Sperimentale, Torino, Italy.
Leukemia. 2005 Apr;19(4):664-70. doi: 10.1038/sj.leu.2403693.
The aim of this study was to investigate the in vitro immunomodulatory effects of zoledronic acid (Zol) on peripheral blood Vgamma9/Vdelta2 (gammadelta) T cells of normal donors and multiple myeloma (MM) patients. gammadelta T cells were stimulated with Zol and low doses of interleukin-2 (IL-2), and then analyzed for proliferation, cytokine production, and generation of effector activity against myeloma cell lines and primary myeloma cells. Proliferation of gammadelta T cells was observed in 100% of normal donors and 50% of MM patients. gammadelta T cells produced IFN-gamma, surface mobilized the CD107a and CD107b antigens, and exerted direct cell-to-cell antimyeloma activity irrespective of the ability to proliferate to Zol and IL-2. The memory phenotype was predominant in the MM gammadelta T cells that proliferated in response to Zol (responders), whereas effector cells were predominant in those that did not (nonresponders). Zol induced antimyeloma activity through the monocyte-dependent activation of gammadelta T cells and by enhancing the immunosensitivity of myeloma cells to gammadelta T cells. Mevastatin, a specific inhibitor of hydroxy-methylglutaryl-CoA reductase, completely abrogated this antimyeloma activity.
本研究的目的是探讨唑来膦酸（Zol）对正常供体和多发性骨髓瘤（MM）患者外周血Vγ9/Vδ2（γδ）T细胞的体外免疫调节作用。用Zol和低剂量白细胞介素-2（IL-2）刺激γδ T细胞，然后分析其增殖、细胞因子产生以及对骨髓瘤细胞系和原发性骨髓瘤细胞的效应活性。在100%的正常供体和50%的MM患者中观察到γδ T细胞增殖。γδ T细胞产生干扰素-γ，表面动员CD107a和CD107b抗原，并且无论对Zol和IL-2增殖的能力如何，都发挥直接的细胞间抗骨髓瘤活性。记忆表型在对Zol增殖的MMγδ T细胞（应答者）中占主导，而效应细胞在未增殖的细胞（无应答者）中占主导。Zol通过单核细胞依赖的γδ T细胞激活以及增强骨髓瘤细胞对γδ T细胞的免疫敏感性来诱导抗骨髓瘤活性。美伐他汀，一种羟甲基戊二酰辅酶A还原酶的特异性抑制剂，完全消除了这种抗骨髓瘤活性。
