利用T淋巴细胞受体ζ链的变化预测肿瘤坏死因子拮抗剂治疗类风湿关节炎的疗效

T cell receptor ζ chain： a biological marker for predicting the therapeutic response to tumour necrosis factor blockade in patients with rheumatoid arthritis

目的探讨ζ链呈低水平表达T淋巴细胞（TCRζmT淋巴细胞）在预测类风湿关节炎（RA）患者对肿瘤坏死因子（TNF）拮抗剂疗效反应中的意义，寻找早期预测患者对生物制剂疗效反应的指标。方法12例血清学阳性的活动性（DAS28〉5．1）RA患者接受了标准方案的英夫利西单抗治疗，在第14周和第30周时根据欧洲抗风湿联盟（EULAR）临床疗效反应标准对患者的疗效进行评价，并将患者分为疗效显著、疗效中等、疗效不住3组。每例患者在英夫利西单抗治疗前以及治疗第14周和第30周时采集外周血，采用流式细胞仪的方法对系列标本中不同细胞亚群、TCRζ的表达水平进行研究，并对TCRζdmT淋巴细胞的移动能力进行分析，并将疗效与TCRζdmT淋巴细胞的变化进行相关分析。结果TCRζdmT淋巴细胞具有很强的移动能力，它们选择性地由外周血向炎症部位移动，导致RA滑液中TCRζdmT淋巴细胞的数量明显多于相应的外周血（P〈0．05）。12例患者中3例疗效显著，6例疗效中等，3例疗效不佳。用药至第30周时临床反应判定为良好的患者，在第14周时外周血中均有CD4＋TCRζdmT淋巴细胞的聚集；而疗效不佳的患者外周血中这群细胞数量反而下降；14周时TCRζdmT淋巴细胞变化的百分数与30周时DAS28评分之间密切相关（r2=0．6835，P〈0．01）。结论TNF拮抗剂是治疗RA有效的药物，用药至第14周时外周血中TCRζdmT淋巴细胞数量的变化可以预测用药至第30周时的疗效，阻止TCRζdmT效应T淋巴细胞由外周血向关节腔的移动是TNF拮抗剂在RA中发挥作用的重要机制。

Objective To explore the potentials of T cells with low expression of ζ （TCRζdmT cells there-after） as a predictor for the therapeutic response to tumor necrosis factor blockade in patients with rheumatoid arthritis （RA）. Methods Twelve active serological positive RA patients （DAS28〉5.1） were recruited and treated with standard protocol of Remicade. At week 14 and week 30, the therapeutic responses to treatment of the patients were assessed as good responders, moderate responders or poor responders. The TCRζ expression in different subpopulation of peripheral lymphocytes was analyzed by flow cytometry at baseline, week 14 and week 30. Results TCRζdmTcells possessed strong migration capability and selectively moved from circulation to the inflammatory sites, which lead to significantly increased TCRζdmT cells in synovial fluid compared to peripheral blood in RA patients （P〈0.05）. According to EULAR therapeutic response criteria, 3 patients （3/12, 25%） were good responders, 6 patients （6/12, 50%） were moderate responders and 3 patients （3/12, 25% ） were poor responders at weak 30. The accumulation of CD4＋ TCRζdmT cells in peripheral blood at week 14 was detected in those good responders, however not in those poor responders. The percentage of changes of TCRζdmT cells at week 14 was closely correlated to DAS28 score at week 30 （r2= 0.6835, P〈0.01）. Conclusion Tumor necrosis factor blockade is effective in the treatment of rheumatoid arthritis. The change of peripheral TCRζdmT cells at week 14 can predict the therapeutic respohse at week 30 in RA patients. Blockade the migration of TCRζdmT lymphocytes from circulation into the joint is one of the important mechanisms of tumor necrosis factor blockade in the treatment of RA.