Combined Treatment of Etanercept and MTX Reverses Th1/Th2, Th17/Treg Imbalance in Patients with Rheumatoid Arthritis
Combined Treatment of Etanercept and MTX Reverses Th1/Th2, Th17/Treg Imbalance in Patients with Rheumatoid Arthritis
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DOI：
10.1007/s10875-011-9542-6
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发表时间：
2011-08-01
影响因子：
9.1
通讯作者：
Zhu Ping
中科院分区：
文献类型：
--
作者：
Chen Lina;Wang Conghua;Zhu Ping
为了探讨依那西普治疗类风湿关节炎（RA）的机制，我们研究了依那西普是否可以逆转Th 1/Th 2和Th 17/调节性T细胞（Treg）失衡，以及这种逆转是否与临床指征的改善有关。我们对40例活动性RA患者进行了为期12周的研究，其中20人单独给予稳定的每周剂量的甲氨蝶呤（MTX），另外10人接受依那西普和MTX的联合治疗。选择10例健康献血员作为对照。采用流式细胞术检测Th 1、Th 2、Th 17和Treg细胞的表达，酶联免疫吸附试验检测血清中相关细胞因子。RA患者CD 4（+）T细胞中IFN-γ（+）Th 1和IL-17（+）Th 17的表达水平显著高于健康对照组，而CD 4（+）CD 25（high）Foxp 3（+）Treg的表达水平显著低于健康对照组。MTX单用或MTX与依那西普联合治疗12周后，外周血Th 17/Treg比值明显下降，而Th 1/Th 2比值无明显差异。联合治疗组Th 17/Treg比值与疾病活动缓解呈正相关。IL-1 β、TNF-α、IL-6、IL-17和IL-23显著降低，而TGF-β显著升高。Th 17/Treg比值与TGF-β呈正相关，而与IL-6呈负相关。依那西普联合MTX可通过使Th 17和Treg及其相关细胞因子的分布正常化来改善RA活动，这可能部分解释了依那西普联合MTX治疗RA的机制。
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-gamma(+)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-1 beta, TNF-alpha, IL-6, IL-17, and IL-23 were significantly decreased, while TGF-beta was significantly elevated. The Th17/Treg ratio was positively related to TGF-beta, 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.