Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity
Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity
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DOI：
10.1172/jci25805
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发表时间：
2006-04-01
影响因子：
15.9
通讯作者：
Zamvil, SS
中科院分区：
文献类型：
--
作者：
Stüve, O;Youssef, S;Zamvil, SS
提高MS治疗疗效的一种方法是确定联合使用可提供附加或协同益处的药物。口服给药的降胆固醇HMG-CoA还原酶抑制剂由于阿托伐他汀可以增强保护性Th 2应答并且具有与醋酸格拉替雷（GA）不同的作用机制，醋酸格拉替雷（GA）是批准用于MS治疗的肠胃外给药的免疫调节剂，我们测试了这些药物的组合是否对EAE有益。使用次优剂量的阿托伐他汀和GA的联合治疗预防或逆转了临床和组织学EAE。在这些小鼠中，促炎性Th 1细胞因子的分泌减少-相反，Th 2细胞因子的分泌增加-但在相同剂量下单独使用每种药物的小鼠中则不然。用次优剂量的阿托伐他汀和GA的组合处理的单核细胞分泌炎性II型细胞因子模式，并且当用作APC时，促进幼稚髓鞘特异性T细胞的Th 2分化。我们的研究结果表明，具有不同免疫调节机制的药物可以以协同方式联合联合收割机治疗CNS自身免疫，并为在MS中测试阿托伐他汀和GA的联合提供了理论基础。
One approach to improving efficacy in MS therapy is to identify medications that provide additive or synergistic benefit in combination. Orally administered cholesterol-lowering HMG-CoA reductase inhibitors (known as statins), which exhibit immunomodulatory properties and are effective in treatment of the MS model EAE, are being tested in MS. As atorvastatin can enhance protective Th2 responses and has a different mechanism of action than glatiramer acetate (GA), a parenterally administered immunomodulatory agent approved for MS treatment, we tested whether the combination of these agents could be beneficial in EAE. Combination therapy using suboptimal doses of atorvastatin and GA prevented or reversed clinical and histologic EAE. Secretion of proinflammatory Th1 cytokines was reduced - and conversely Th2 cytokine secretion was increased - in these mice, but not in mice treated with each drug alone at the same doses. Monocytes treated with the combination of suboptimal doses of atorvastatin and GA secreted an and inflammatory type II cytokine pattern and, when used as APCs, promoted Th2 differentiation of naive myelin-specific T cells. Our results demonstrate that agents with different mechanisms of immune modulation can combine in a synergistic manner for the treatment of CNS autoimmunity and provide rationale for testing the combination of atorvastatin and GA in MS.