Normandie Univ, UNIROUEN, Inserm U 1245, Rouen, France.
Normandie Univ, UNIROUEN, Inserm U 1234, Rouen, France.
PLoS One. 2020 Aug 6;15(8):e0237143. doi: 10.1371/journal.pone.0237143. eCollection 2020.
Abatacept acts as a competitive inhibitor of the CD28/(CD80/86) costimulation signal required for T cell activation. Mechanisms of action of abatacept have not been fully investigated. The objective of this study was to provide detailed insight into the mode of action of Abatacept based on gene expression data.
In this ancillary study from the APPRAISE trial, we investigated the global molecular effects of Abatacept in whole blood samples collected prospectively in biologic naive rheumatoid arthritis patients (n = 19) at baseline and 6 months after the initiation of Abatacept therapy concomitant with methotrexate. Whole human genome microarrays (4x44K) were performed on both baseline and 6-month samples from responders and non-responders patients categorized according to EULAR criteria. T-test with Benjamini-Hochberg correction was performed to identify significant gene expression changes. Gene Ontology and Single Experiment Analysis tools allowed us to highlight specific biological mechanisms involved in methotrexate/Abatacept.
In methotrexate/Abatacept responders, 672 genes were significantly (q<0.05) dysregulated at 6 months compared to baseline. Correlation analysis highlighted 19 genes whose dysregulations were significantly associated with disease activity variation (p<0.05) and whose functions were associated with proliferation, apoptosis of cells and mitochondrial metabolism, suggesting a restoration of oxidative signaling. The other 653 gene expression changes were relative to direct or indirect effects of methotrexate/Abatacept treatment and were significantly (p<0.005) involved in pathways relative to mRNA processing, proteasome, angiogenesis, apoptosis and TCR signaling. This study highlights new mechanisms of action of methotrexate/Abatacept and may provide new therapeutic targets to prevent autoimmunity in rheumatoid arthritis.
阿巴西普作为 T 细胞激活所需的 CD28/(CD80/86)共刺激信号的竞争性抑制剂发挥作用。阿巴西普的作用机制尚未完全研究清楚。本研究的目的是基于基因表达数据提供对阿巴西普作用模式的详细了解。
在 APPRAISE 试验的这项辅助研究中，我们在生物治疗-naive 的类风湿关节炎患者（n=19）的前瞻性全血样本中调查了阿巴西普的整体分子作用，这些患者在开始接受阿巴西普联合甲氨蝶呤治疗时收集了基线和 6 个月时的样本。根据 EULAR 标准，对来自应答者和无应答者患者的基线和 6 个月样本进行了全人类基因组微阵列（4x44K）分析。采用 T 检验和 Benjamini-Hochberg 校正法来识别基因表达变化的显著差异。GO 和单实验分析工具使我们能够突出参与甲氨蝶呤/阿巴西普治疗的特定生物学机制。
在甲氨蝶呤/阿巴西普应答者中，与基线相比，有 672 个基因在 6 个月时显著（q<0.05）失调。相关性分析突出了 19 个基因，这些基因的失调与疾病活动变化显著相关（p<0.05），其功能与细胞增殖、凋亡和线粒体代谢有关，这表明氧化信号得到了恢复。其他 653 个基因表达变化与甲氨蝶呤/阿巴西普治疗的直接或间接作用有关，与 mRNA 处理、蛋白酶体、血管生成、凋亡和 TCR 信号转导等途径显著相关（p<0.005）。这项研究强调了甲氨蝶呤/阿巴西普的新作用机制，并可能为预防类风湿关节炎中的自身免疫提供新的治疗靶点。
