Department of Clinical Immunology, State Key Discipline of Cell Biology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, People's Republic of China.
J Clin Immunol. 2011 Aug;31(4):596-605. doi: 10.1007/s10875-011-9542-6. Epub 2011 May 12.
To explore the mechanism of Etanercept in the treatment of rheumatoid arthritis (RA), we investigated whether the Th1/Th2 and Th17/regulatory T cells (Treg) imbalance could be reversed by Etanercept and whether the reversal was related to the improvement of clinical indications.
We conducted a 12-week study in 40 active RA patients, of whom 20 were given a stable weekly dose of methotrexate (MTX) alone and the other ten received a combined therapy of Etanercept and MTX. Ten healthy donors were chosen as controls. Frequencies of Th1, Th2, Th17, and Treg were quantified using flow cytometry, and related serum cytokines were detected by enzyme-linked immunosorbent assay. The composite 28-joint count Disease Activity Score, erythrocyte sedimentation rate, and C-reactive protein were assessed at each visit.
Percentages of IFN-γ(+)Th1 and IL-17(+)Th17 among CD4(+) T cells were significantly higher, while CD4(+)CD25(high)Foxp3(+) Treg were significantly lower in RA patients compared with those in healthy control. After 12 weeks of therapy of MTX single or combination of MTX and Etanercept, the circulating Th17/Treg ratio significantly decreased, while no significant difference was observed in Th1/Th2 ratio. In combined therapy group, the Th17/Treg ratio was positively correlated with the remittance of disease activity. IL-1β, TNF-α, IL-6, IL-17, and IL-23 were significantly decreased, while TGF-β was significantly elevated. The Th17/Treg ratio was positively related to TGF-β, but negatively correlated with IL-6.
Etanercept in combination with MTX ameliorates RA activity by normalizing the distribution of Th17 and Treg, and their related cytokines, which may partly explain the mechanism of combined therapy of Etanercept plus MTX in RA treatment.
探讨依那西普治疗类风湿关节炎（RA）的作用机制，观察依那西普能否纠正 RA 患者的 Th1/Th2 及 Th17/Treg 失衡，及其与临床指标改善的关系。
选择 40 例活动期 RA 患者，分为 MTX 单药组（n=20）和 MTX+依那西普组（n=20），另选择 10 名健康志愿者作为正常对照。采用流式细胞术检测 Th1、Th2、Th17 和 Treg 细胞比例，酶联免疫吸附法检测相关细胞因子。每 4 周随访 1 次，观察临床疗效，检测红细胞沉降率（ESR）、C 反应蛋白（CRP）、28 关节疾病活动评分（DAS28）。
与正常对照组比较，RA 患者外周血 CD4+IFN-γ+Th1 及 CD4+IL-17+Th17 细胞比例明显升高，CD4+CD25+Foxp3+Treg 细胞比例明显降低。MTX 单药或联合依那西普治疗 12 周后，患者外周血 Th17/Treg 比例明显下降，Th1/Th2 比例无明显变化；联合治疗组患者 Th17/Treg 比例与疾病活动度改善呈正相关。治疗后患者血清 IL-1β、TNF-α、IL-6、IL-17、IL-23 水平明显下降，TGF-β 水平明显升高；Th17/Treg 比例与 TGF-β 呈正相关，与 IL-6 呈负相关。
依那西普联合 MTX 治疗 RA 可通过调节 Th17/Treg 及其相关细胞因子的失衡而改善疾病活动度，这可能是依那西普联合 MTX 治疗 RA 的作用机制之一。
