重组人细胞毒T淋巴细胞相关抗原4抗体融合蛋白对类风湿关节炎患者外周血T淋巴细胞的影响

The effect of recombinant human CTLA-4Ig fusion protein on T lymphocytes in active rheumatoid arthritis patients

目的探讨应用重组人细胞毒T淋巴细胞相关抗原（CTLA）-4抗体融合蛋白（rhCTLA-4Ig）治疗类风湿关节炎（RA）患者的临床疗效及对患者外周血辅助性T细胞17（Th17）和调节性T细胞的影响。方法48例处于活动期的RA患者按1：1的比例随机分为治疗组和对照组，治疗组接受12周的rhCTLA．41g（10mg／kg）治疗；对照组接受12周的安慰剂治疗。以美国风湿病学会RA20％改善标准（ACR20）及疾病活动指数（DAS）28观察临床疗效；同时用流式细胞术检测受试者外周血Th17的变化，反转录聚合酶链反应（RT．PCR）检测外周血单个核细胞中FoxP3表达水平的变化。采用t检验和r检验进行统计学分析。结果①治疗后12周治疗组24例中18例达ACR20改善，达ACR20改善的患者比例为75％，对照组中有1例（4％）达ACR20改善，2组差异有统计学意义W=25．176，P〈0．01）；治疗后12周DAS28评分治疗组与对照组比较差异有统计学意义（分别为3．0±0．7，6．9±0．7，f=12．39，P〈0．01）。②治疗后治疗组RA患者外周血表达IL．17A的单个核细胞为（0．22±0．20）％，对照组为（1．63±0．47）％，治疗组较对照组显著下降，差异有统计学意义（￡=5．61，P〈0．05）。③治疗组FoxP3mRNA的表达（0．88±0．18）较对照组（0．24±0．05）明显增高，差异有统计学意义（t=7．56，P〈0．01）。结论rhcTLA．4Ig治疗RA临床表现和实验室指标明显改善，且外周血中Th17细胞及调节性T细胞的失衡程度有明显恢复。

Objective To discuss the therapeutic effect of recombinant human CTLA-4Ig fusion protein （rhCTLA-4Ig） on rheumatoid arthritis （RA） patients and the change of T helper cells 17 （Th17） and regulatory T （Treg） cells. Methods Forty-eight active RA patients were randomly divided into the treatment group and the control group. Treatment group received 12 weeks of infusions of rhCTLA-4Ig （10 mg/kg）, while the control group received 12 weeks of infusions of placebo. The changes of expression levels of Thl7 cell were detected by flow cytometry. The changes of expression level of FoxP3 in monocytes of the peripheral blood were examined by RT-PCR. T test andx2 test were used for statistical analysis. Results （~ Eighteen of 24 cases in treatment group showed good ACR20 changes after 12 weeks, the effective rate （75%） was significantly higher than that of the control group （1/24, 4%）. After treatment, DAS28 score of the treatment group （3.0±0.7） was significantly lower than that of the control group （6.9±0.7） （t=-12.39, P〈0.01 ）. 2） Compared with the Thl7 monocytes of the peripheral blood from active RA patients of treatment group after therapy （0.22±0.20）%, the Thl7 monocytes of peripheral blood from active RA patients of the control group （1.63± 0.47）% were higher （t=5.61, P〈0.05）. （3） Compared with the FoxP3 mRNA of the control group （0.24±0.05）, that of the treatment group （0.88±0.18） was significantly higher after therapy （t=7.56, P〈0.01 ）. Conclusion The clinical parameters of RA patients have improved significantly after the treatment,and the Thl7 and Treg cells balance is also restored after rhCTLA-4Ig therapy.