Molecular profiling of glatiramer acetate early treatment effects in multiple sclerosis
Molecular profiling of glatiramer acetate early treatment effects in multiple sclerosis
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DOI：
10.3233/dma-2009-0651
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发表时间：
2009-01-01
期刊：
影响因子：
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通讯作者：
Michael, Gurevich
中科院分区：
文献类型：
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作者：
Anat, Achiron;Anna, Feldman;Michael, Gurevich
背景：醋酸格拉替雷（GA，Copaxone (R)）对复发缓解型多发性硬化症（RRMS）的临床病程具有有益作用。然而，GA 效应的确切分子机制尚不完全清楚。 目的：通过外周血单核细胞 (PBMC) 的微阵列分析来表征治疗 3 个月内 RRMS 患者中 GA 的分子效应。 方法：使用包含 14,500 个特征良好的人类基因的 Affimetrix (U133A-2) 微阵列测定 RRMS 患者在开始 GA 治疗前和 3 个月后的基因表达谱。使用基因功能注释、富集分析和通路重建生物信息学软件构建了在 RRMS 中运行的 GA 诱导的生物收敛通路的大多数信息基因 (MIG)。通过 qRT-PCR 和 FACS 进行 mRNA 和蛋白质水平的验证。结果：GA 诱导了特定的基因表达分子特征，其中包括治疗 3 个月内 480 个基因表达的改变； 262个基因上调，218个基因下调。 GA 作用的主要收敛机制与抗原激活的细胞凋亡、炎症、粘附和 MHC I 类抗原呈递有关。结论：我们的研究结果表明，GA 治疗会诱导免疫调节基因表达模式的改变，这对于治疗三个月后抑制疾病活动非常重要，并且可以用作 GA 活性的分子标记。
Background: Glatiramer acetate (GA, Copaxone (R)) has beneficial effects on the clinical course of relapsing-remitting multiple sclerosis (RRMS). However, the exact molecular mechanisms of GA effects are only partially understood.Objective: To characterized GA molecular effects in RRMS patients within 3 months of treatment by microarray profiling of peripheral blood mononuclear cells (PBMC).Methods: Gene-expression profiles were determined in RRMS patients before and at 3 months after initiation of GA treatment using Affimetrix (U133A-2) microarrays containing 14,500 well-characterized human genes. Most informative genes (MIGs) of GA-induced biological convergent pathways operating in RRMS were constructed using gene functional annotation, enrichment analysis and pathway reconstruction bioinformatic softwares. Verification at the mRNA and protein level was performed by qRT-PCR and FACS.Results: GA induced a specific gene expression molecular signature that included altered expression of 480 genes within 3 months of treatment; 262 genes were up-regulated, and 218 genes were down-regulated. The main convergent mechanisms of GA effects were related to antigen-activated apoptosis, inflammation, adhesion, and MHC class-I antigen presentation.Conclusions: Our findings demonstrate that GA treatment induces alternations of immunomodulatory gene expression patterns that are important for suppression of disease activity already at three months of treatment and can be used as molecular markers of GA activity.