Mindur John E, Valenzuela Reuben M, Yadav Sudhir K, Boppana Sridhar, Dhib-Jalbut Suhayl, Ito Kouichi
Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
J Neuroimmunol. 2017 Mar 15;304:21-28. doi: 10.1016/j.jneuroim.2016.07.004. Epub 2016 Jul 17.
Glatiramer acetate (GA) is an FDA-approved efficacious drug for the treatment of relapsing-remitting multiple sclerosis (RRMS). However, this treatment is not effective for all RRMS patients. Therefore, it is important to identify reliable biomarkers that can predict a beneficial clinical response to GA therapy. Since an increase in IL-27 has been demonstrated to suppress autoimmune and allergic diseases of inflammatory origin, we examined the effect of GA on the production of IL-27. We observed that IL-27 production in PBMCs cultured with GA was heterogeneous amongst MS patients and healthy donors (HD), and thus, defined these MS patients as either efficient, weak, or non-IL-27 producers. Interestingly, GA could induce the expression of the IL-27p28 subunit more efficiently than the IL-27 EBI3 subunit, and the production of IL-27 depended on MHC class II binding by GA. In addition, we found that GA could augment Toll-like receptor (TLR)-mediated IL-27 production. Importantly, serum production of IL-27 and IL-10 was significantly increased at 6months during GA therapy in clinical responders to GA, but not in GA non-responders. Altogether, our data suggest that GA-induced IL-27 may represent a therapeutic mechanism of GA-mediated immunomodulation and that GA-mediated IL-27 production in PBMCs is worth exploring as a biomarker to screen for GA responders prior to the initiation of GA treatment.
醋酸格拉替雷（GA）是一种经美国食品药品监督管理局（FDA）批准用于治疗复发缓解型多发性硬化症（RRMS）的有效药物。然而，这种治疗方法并非对所有RRMS患者都有效。因此，识别能够预测对GA治疗产生有益临床反应的可靠生物标志物非常重要。由于已证明白细胞介素-27（IL-27）的增加可抑制炎症性自身免疫和过敏性疾病，我们研究了GA对IL-27产生的影响。我们观察到，在用GA培养的外周血单核细胞（PBMC）中，MS患者和健康供体（HD）的IL-27产生存在异质性，因此，将这些MS患者定义为高效、低效或非IL-27产生者。有趣的是，GA诱导IL-27 p28亚基的表达比诱导IL-27 EBI3亚基更有效，并且IL-27的产生取决于GA与主要组织相容性复合体II类（MHC II）的结合。此外，我们发现GA可以增强Toll样受体（TLR）介导的IL-27产生。重要的是，在GA治疗6个月时，GA临床反应者的血清IL-27和IL-10水平显著升高，而GA无反应者则没有。总之，我们的数据表明，GA诱导的IL-27可能代表GA介导的免疫调节的一种治疗机制，并且在开始GA治疗之前，PBMC中GA介导的IL-27产生作为筛选GA反应者的生物标志物值得探索。
