Effector gammadelta T cells and tumor cells as immune targets of zoledronic acid in multiple myeloma.
Effector gammadelta T cells and tumor cells as immune targets of zoledronic acid in multiple myeloma.
复制标题
效应γδ T 细胞和肿瘤细胞作为多发性骨髓瘤中唑来膦酸的免疫靶标。
作者：
S. Mariani;M. Muraro;F. Pantaleoni;F. Fiore;B. Nuschak;S. Peola;M. Foglietta;A. Palumbo;M. Coscia;B. Castella;B. Bruno;R. Bertieri;L. Boano;M. Boccadoro;M. Massaia
本研究旨在探讨唑来膦酸（Zol）对正常人和多发性骨髓瘤（MM）患者外周血V γ 9/V δ 2（γ δ）T细胞的体外免疫调节作用。用Zol和低剂量的白细胞介素-2（IL-2）刺激γ δ T细胞，然后分析增殖、细胞因子产生和针对骨髓瘤细胞系和原代骨髓瘤细胞的效应物活性的产生。在100%的正常供体和50%的MM患者中观察到γ δ T细胞增殖。γ δ T细胞产生IFN-γ，表面动员CD 107 a和CD 107 b抗原，并发挥直接的细胞间抗骨髓瘤活性，而不管增殖为Zol和IL-2的能力。记忆表型在响应Zol而增殖的MM γ δ T细胞中占主导地位（应答者），而效应细胞在不响应Zol的MM γ δ T细胞中占主导地位（无应答者）。Zol通过γ δ T细胞的单核细胞依赖性活化和增强骨髓瘤细胞对γ δ T细胞的免疫敏感性诱导抗骨髓瘤活性。美伐他汀是一种特异性的羟甲基戊二酰辅酶A还原酶抑制剂，完全消除了这种抗骨髓瘤活性。
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.