Statins prevent bisphosphonate-induced γ,δ-T-cell proliferation and activation in vitro
Statins prevent bisphosphonate-induced γ,δ-T-cell proliferation and activation in vitro
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DOI：
10.1359/jbmr.0301230
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发表时间：
2004-02-01
影响因子：
6.2
通讯作者：
Rogers, MJ
中科院分区：
文献类型：
--
作者：
Thompson, K;Rogers, MJ
简介：急性期反应是静脉注射含氮双膦酸盐药物（N-BPs）治疗代谢性骨病的主要不良反应。这种效应最近被归因于它们作为非肽抗原的作用和对γ、δ T细胞的直接刺激。然而，因为N-BP是法尼基二磷酸（FPP）合酶的有效抑制剂，所以它们可能由于甲羟戊酸途径中FPP合酶上游的中间体（例如异戊烯基二磷酸/二甲基烯丙基二磷酸，其是已知的γ，δ-T细胞激动剂）的积累而引起γ，δ-T细胞的间接活化。从健康志愿者中分离外周血单核细胞（PBMC），并在白细胞介素（IL）-2存在下用N-BP、他汀类药物或甲羟戊酸途径的中间体/抑制剂处理7天。结果和结论：N-BP刺激人PBMC培养物中CD 3（+）γ，δ-T细胞增殖的能力与抑制FPP合酶的能力相匹配。通过美伐他汀或洛伐他汀阻止γ、δ-T细胞增殖和活化（干扰素γ [IFN γ]和TNF α释放），美伐他汀或洛伐他汀抑制FPP合酶上游的HMG-CoA还原酶并阻止异戊烯基二磷酸/二甲基烯丙基二磷酸的合成。去氧洛伐他汀，一种不能抑制HMG-CoA还原酶的洛伐他汀类似物，没有克服N-BP的刺激作用。此外，他汀类药物不能阻止合成的γ、δ-T细胞激动剂或抗CD 3抗体对γ、δ-T细胞的活化。总之，这些观察结果表明，N-BP间接刺激γ，δ-T细胞的增殖和活化，这是由FPP合酶的抑制和PBMC中异戊烯基二磷酸/二甲基烯丙基二磷酸的细胞内积累引起的。由于γ、δ-T细胞的活化可能是双膦酸盐治疗急性期反应的起始事件，因此他汀类药物的联合给药可能是预防这种不良反应的有效方法。
Introduction: The acute phase response is the major adverse effect of intravenously administered nitrogen-containing bisphosphonate drugs (N-BPs), used in the treatment of metabolic bone diseases. This effect has recently been attributed to their action as non-peptide antigens and direct stimulation of gamma,delta-T-cells. However, because N-BPs are potent inhibitors of farnesyl diphosphate (FPP) synthase, they could cause indirect activation of gamma,delta-T-cells owing to the accumulation of intermediates upstream of FPP synthase in the mevalonate pathway, such as isopentenyl diphosphate/dimethylallyl diphosphate, which are known gamma,delta-T-cell agonists.Materials and Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from healthy volunteers and treated with N-BP, statin, or intermediates/inhibitors of the mevalonate pathway for 7 days in the presence of interleukin (IL)-2. Flow cytometric analysis of the T-cell-gated population was used to quantify the proportion of gamma,delta-T-cells in the CD3(+) population.Results and Conclusions: The ability of N-BPs to stimulate proliferation of CD3(+) gamma,delta-T-cells in human PBMC cultures matched the ability to inhibit FPP synthase. gamma,delta-T-cell proliferation and activation (interferon gamma [IFNgamma] and TNFalpha release) was prevented by mevastatin or lovastatin, which inhibit HMG-CoA reductase upstream of FPP synthase and prevent the synthesis of isopentenyl diphosphate/dimethylallyl diphosphate. Desoxolovastatin, an analog of lovastatin incapable of inhibiting HMG-CoA reductase, did not overcome the stimulatory effect of N-BP. Furthermore, statins did not prevent the activation of gamma,delta-T-cells by a synthetic gamma,delta-T-cell agonist or by anti-CD3 antibody. Together, these observations show that N-BPs indirectly stimulate the proliferation and activation of gamma,delta-T-cells caused by inhibition of FPP synthase and intracellular accumulation of isopentenyl diphosphate/ dimethylallyl diphosphate in PBMCs. Because activation of gamma,delta-T-cells could be the initiating event in the acute phase response to bisphosphonate therapy, co-administration of a statin could be an effective approach to prevent this adverse effect.