小剂量雷帕霉素治疗活动性类风湿关节炎临床疗效及重建调节性T细胞介导的免疫耐受的研究

Low-dose rapamycin: clinical efficacy in treatment of active rheumatoid arthritis and reconstruction of Treg cell-mediated immune tolerance

目的研究小剂量雷帕霉素治疗活动性类风湿关节炎(RA)患者的临床疗效及安全性,观察其对调节性T细胞(Treg细胞)介导的免疫耐受的重建。方法选取活动性RA患者62例按2∶1随机分为雷帕霉素组42例和对照组20例,2组均给予改善病情抗风湿药(DMARDs)及/或小剂量激素,雷帕霉素组加用雷帕霉素0.5mg1次/隔日,2组患者分别于0、3、6、12周进行临床和常规实验室指标评估,并在0、12周采用流式细胞术检测患者外周血以CD4^+CD25^+Foxp3^+Treg细胞、辅助性T细胞(CD4^+IL-17^+Th)17为主的CD4^+T亚群细胞绝对计数及百分比,比较2组之间及治疗前后患者的临床及实验室指标,并记录不良反应。结果共55例患者完成研究,分为雷帕霉素组37例和对照组18例,经12周治疗后2组28个关节疾病活动脂数(DAS28)评分、肿胀关节数(SJC)、关节压痛数(TJC)、红细胞沉降率(ESR)均下降,差异有统计学意义(P<0.05);2组中仅雷帕霉素组的免疫抑制用量明显少于传统治疗组,且2组均无不可逆的不良反应出现;雷帕霉素组Treg细胞、Th17绝对计数显著高于对照组[12周2组Treg分别为(29±23)个/μl和(16±16)个/μl,P=0.042;Th17分别为(7.3±5.5)个/μl和(3.5±2.4)个/μl,P=0.011];雷帕霉素组Treg细胞、Th17细胞绝对计数治疗前后无明显差异,而对照组2种细胞绝对计数显著下降[Treg:0周(35±20)个/μl,12周(16±16)个/μl,P=0.016;Th17:0周(8.9±4.2)个/μl,12周(3.5±2.4)个/μl,P=0.028]。结论DMARDs药物可能通过减少RA患者Treg细胞、Th17细胞数缓解病情,而加用小剂量雷帕霉素可以明显提高RA患者外周血中Treg细胞水平,提示雷帕霉素可能通过重建Treg细胞介导的免疫耐受缓解病情,为活动性RA的治疗提供新思路。

Objective To investigate the clinical efficacy and safety of low-dose rapamycin in patients with active rheumatoid arthritis (RA) and its reconstructive effect of regulatory T cell (Treg)-mediated immune tolerance. Methods Sixty-two patients with active RA were enrolled in this study, randomly divided into the rapamycin group (n=42) and control group (n=20), all given disease-modifying antirheumatic drugs (DMARDs) with or without small-dose steroids. The Rapamycin group was additionally given with 0.5 mg Rapamycin once every two days. The two groups were evaluated for clinical and routine laboratory indicators at 0, 3, 6, and 12 weeks. At at 0 and 12 weeks,flow cytometry was used to examinethe absolute counts and percentages of peripheral blood CD4+T subset, focusing onCD4^+ CD25^+Foxp3+ Treg cells and helper T cells CD4^+IL-17^+Th17. Clinical and laboratory indicators were compared between the two groups and before and after treatment. Adverse reactions were recorded. Results A total of 55 patients [rapamycin group (n=37) and control group (n=18)] completed the study. After 12 weeks of treatment, the DAS28 score, swollen joint count(SJC), tender joint count(TJC), and erythrocyte sedimentation rate (ESR) were significantly decreased in the both groups(P<0.05). The dose of DMARDs in the rapamycin group was significantly lower than that in the controlgroup. There were no irreversible adverse events recorded in either group. The absolute counts of Treg cells and Th17 in the rapamycin group were significantly higher than those in the control group [at 12 weeks, Treg cells:(29±23)/μl vs (16±16)/μl, P=0.042;Th17:(7.3±5.5)/μl vs (3.5±2.4)/μl, P=0.011]. There was no significant difference in absolute counts of Treg cells and Th17 cells in the rapamycin group before and after treatment, while the absolute counts of the two cells in the control group weredecreased significantly [Treg: 0 weeks,(35±20)/μl, 12 weeks,(16±16)/μl, P=0.016;Th17: 0 weeks,(8.9±4.2)/μl, 12 weeks,(3.5±2.4)/μl, P=0.028]. Conclusion DMARDs may alleviate the disease severityby reducing the numbers of Treg cells and Th17 cells in RA patients. Addition of low-dose rapamycin may significantly increase the peripheral blood level of Treg cells in RA patients, suggesting that rapamycin may ameliorate RA by reconstructing Treg-mediated immune tolerance. This provide snew ideation for treatment of active RA.