Therapy with anti-TNFα Antibody Enhances Number and Function of Foxp3+ Regulatory T Cells in Inflammatory Bowel Diseases
Therapy with anti-TNFα Antibody Enhances Number and Function of Foxp3+ Regulatory T Cells in Inflammatory Bowel Diseases
复制标题
DOI：
10.1002/ibd.21308
复制
发表时间：
2011-01-01
影响因子：
4.9
通讯作者：
Kaiserlian, Dominique
中科院分区：
文献类型：
--
作者：
Boschetti, Gilles;Nancey, Stephane;Kaiserlian, Dominique
背景：炎症性肠病 (IBD) 与 TNF α 上调、促炎效应 T 细胞 (Teffs) 过度激活以及调节性 CD4(+)CD25(+)Foxp3(+) T 细胞 (Treg) 的低效控制有关。这项前瞻性研究的目的是探讨抗 TNF α 抗体（英夫利昔单抗或阿达木单抗）治疗 IBD 患者对 Tregs 频率、表型和抑制功能的短期影响。 方法：对活动性 IBD 患者（包括 16 例克罗恩病患者和 9 例溃疡性结肠炎患者）进行抗 TNF α mAb 治疗。在第一次注射之前和之后两周收获 PBMC。采用流式细胞术分析循环CD4(+)CD25(+)Foxp3(+)Treg的频率和表型，并通过纯化的CD4(+)CD25(+)CD127(-)Treg抑制同种异体CD4(+)CD25(-)Teffs增殖的能力来评估其抑制功能。活动性 IBD 患者低于对照组（分别为 2.8% +/- 0.4% 与 4.6% +/- 0.6%；P = 0.01）。在第一次抗TNFα输注后第14天，IBD患者循环Tregs的频率显着增强（治疗前为4.0%+/-0.5%对比2.8%+/-0.4%；P = 0.001），Foxp3表达强度增加2至3倍。此外，英夫利昔单抗治疗增强了循环Treg的抑制功能，如以1:8 Treg/Teff比率抑制Teff增殖所示（治疗后28% +/- 5% vs. 66% +/- 10%；P = 0.04）。 结论：这些数据表明，活动性IBD的抗TNF α治疗可迅速提高血液中功能性Foxp3(+) Tregs的频率，并增强其抑制功能。这表明 Treg 增强可能代表了 IBD 中抗 TNF α 生物疗法的意外结果。
Background: Inflammatory bowel diseases (IBDs) are associated with up-regulation of TNF alpha, hyperactivation of proinflammatory effector T cells (Teffs) and inefficient control by regulatory CD4(+)CD25(+)Foxp3(+) T cells (Tregs). The aim of this prospective study was to investigate the short-term impact of treatment of IBD patients with anti-TNF alpha antibodies (infliximab or adalimumab) on the frequency, phenotype, and suppressive function of Tregs.Methods: Active IBD patients including 16 with Crohn's disease and 9 with ulcerative colitis were treated with anti-TNF alpha mAb. PBMCs were harvested immediately before and 2 weeks after the first injection. The frequency and phenotype of circulating CD4(+)CD25(+)Foxp3(+) Tregs were analyzed by flow cytometry, and their suppressive function was assessed by the ability of purified CD4(+)CD25(+)CD127(-) Tregs to inhibit the proliferation of allogenic CD4(+)CD25(-) Teffs.Results: CD4(+)CD25(+)Foxp3(+) Treg frequency was significantly lower in active IBD patients than in controls (2.8% +/- 0.4% vs. 4.6% +/- 0.6%, respectively; P = 0.01). On day 14 following the first anti-TNF alpha infusion, the frequency of circulating Tregs was significantly enhanced in IBD patients (4.0% +/- 0.5% vs. 2.8% +/- 0.4%, before treatment; P = 0.001), with a 2- to 3-fold increase in the intensity of Foxp3 expression. In addition, infliximab treatment enhanced the suppressive function of circulating Tregs, as shown by inhibition of Teff proliferation at a 1:8 Treg/Teff ratio (28% +/- 5% vs. 66% +/- 10%, after treatment; P = 0.04).Conclusions: These data demonstrate that anti-TNF alpha treatment of active IBD rapidly enhances the frequency of functional Foxp3(+) Tregs in blood and potentiates their suppressive function. This indicates that Treg potentiation may represent an unanticipated outcome of anti-TNF alpha biotherapy in IBD.