辛伐他汀对实验性变态反应性脑脊髓炎和多发性硬化单个核细胞增殖的影响

摘要

目的 研究他汀类药物对致敏实验性变态反应性脑脊髓炎(EAE)模型及多发性硬化(MS)患者单个核细胞增殖的影响,以及与人重组干扰素β1a(INFβ-1a)的协同作用.方法 (1)建立EAE模型,取其脾脏制成单个核细胞悬液,分别予ConA、LPS及MOG刺激,同时予不同浓度辛伐他汀、INFβ-1a进行干预,3H-TdR掺入法检测辛伐他汀对单个核细胞增殖的影响及两者协同作用.(2)根据McDonald(2005年)诊断标准,收集确诊为MS的患者15例,要求在近期均未行特殊免疫治疗,分离外周血单个核细胞,同上进行药物干预及检测.结果 (1)辛伐他汀以剂量依赖的方式抑制了致敏EAE小鼠脾单个核细胞的增殖;常规剂量的辛伐他汀对致敏EAE小鼠脾单个核细胞增殖有明显抑制作用,低剂量的两药联用对经ConA、MOG致敏的EAE小鼠脾单个核细胞抑制增殖作用增强,与阴性对照组相比,差异均有统计学意义(P＜0.05或0.01).(2)辛伐他汀以剂量依赖的方式抑制了致敏MS患者外周血单个核细胞的增殖;常规剂量的辛伐他汀对致敏MS患者外周血单个核细胞增殖均有明显抑制作用,与阴性对照组相比,差异有统计学意义(P＜0.05或0.01);低剂量的辛伐他汀与不同剂量INFβ-1a联用具协同作用.结论 他汀类药物是有效的免疫调节剂,不仅调节异常的细胞免疫及体液免疫,还可协同INFβ-1a抑制致敏的单个核细胞增殖.%To investigate the effects of simvastatin on peripheral mononuclear cells (PMNCs) proliferation inexperimental allergic encephalomyelitist EAE) and in patients with multiple sclerosis (MS).Mouse EAE model was es-tablished; splenocytes were isolated from EAE mice and stimulated with conA, LPS or MOG. Splenocytes were treated with simvastatin, INF p-1a, or medium alone as a control, then the thymidine incorporation was measured with a liquid scintillation counter. Data were expressed as mean counts per minutet CPM) derived from triplicate cultures. Blood samples were drawn from 15 patients with MS defined by McDonald's diagnostic criteria(2005). Exclusion criteria included previous treatment with im-munomodulatory, immunosuppressive, or cholesterollowering medications, and treatment with steroids within 30 days of blood collection. PBMCs were isolated on a discontinuous density gradient and the rest of the experiment method as above. Simvastatin inhibited conA-, LPS-, and MOG-induced splenic proliferative responses of EAE mice in vitro in a dose-dependent manner. Combination therapy using suboptimal doses of simvastatin and INF(3-1a resulted in an additive suppression of splenic proliferative responses. Statins inhibited proliferation of PBMC from MS patients in a dose-dependent manner. Combination therapy using suboptimal doses of simvastatin and different concentrations of INF(31a resulted in an additive suppression of PBMC proliferation.ConclusionStatins are effective immunomodulators in vitro and may exert synergistic effects with INF(3-1a.