英夫利昔单抗治疗后 IBD 患者血液和肠道黏膜中 Foxp3 表达的相互变化。

Reciprocal changes of Foxp3 expression in blood and intestinal mucosa in IBD patients responding to infliximab.

机构信息

Laboratory of Experimental Immunology, Catholic University of Leuven, Leuven, Belgium.

出版信息

Inflamm Bowel Dis. 2010 Aug;16(8):1299-310. doi: 10.1002/ibd.21229.

DOI:10.1002/ibd.21229

PMID:20196149

Abstract

BACKGROUND

Immune therapies may act in inflammatory bowel diseases (IBD) by modulating regulatory T cells (Tregs). Therefore, we investigated the effect of infliximab (IFX) therapy on Forkhead box protein3 (Foxp3) T cells in blood and intestinal mucosa from Crohn's disease (CD) and ulcerative colitis (UC).

METHODS

Forty patients with active IBD (23 CD / 17 UC) were treated with IFX 5 mg/kg intravenously at weeks 0, 2, 6, and each 8 weeks thereafter. Blood samples were obtained before every infusion and T-lymphocyte subsets were characterized by flow cytometry. Foxp3 expression in intestinal biopsies from 43 patients with active IBD (19 CD / 24 UC) before and after IFX infusion and from 6 controls were assessed by quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. Plasma C-reactive protein (CRP), clinical response, and endoscopic healing data were collected in parallel.

RESULTS

IFX therapy resulted in a significant and sustained relative increase of CD4(+)CD25(+)Foxp3(+) Treg and of CD4(+)CD25(-)Foxp3(+) Treg cells in peripheral blood (both P < 0.0001 compared to baseline), particularly in responders (both P < 0.05 compared to nonresponders). The change in CRP over time inversely correlated with the increase of CD25(+)Foxp3(+) cells (P < 0.001, r = -0.39) and durable clinical response was associated with a sustained increase of circulating Foxp3(+) cells. Surprisingly, IFX therapy downregulated mucosal mRNA and protein expression of Foxp3 in UC and CD responders (both P < 0.001) but not in nonresponders.

CONCLUSIONS

IFX therapy has opposite effects in Foxp3(+) Treg cells in blood and gut mucosa, which suggests a redistribution of this important T-cell subset.

摘要

背景

免疫疗法可能通过调节调节性 T 细胞（Tregs）在炎症性肠病（IBD）中发挥作用。因此，我们研究了英夫利昔单抗（IFX）治疗对克罗恩病（CD）和溃疡性结肠炎（UC）患者血液和肠道黏膜中叉头框蛋白 3（Foxp3）T 细胞的影响。

方法

40 例活动性 IBD 患者（23 例 CD/17 例 UC）接受 IFX 5mg/kg 静脉滴注，分别在 0、2、6 周和此后每 8 周一次。在每次输注前采集血样，并通过流式细胞术对 T 淋巴细胞亚群进行特征分析。通过定量逆转录聚合酶链反应和免疫组织化学评估 43 例活动性 IBD 患者（19 例 CD/24 例 UC）在 IFX 输注前后和 6 例对照者的肠道活检中 Foxp3 的表达。同时收集血浆 C 反应蛋白（CRP）、临床反应和内镜愈合数据。

结果

IFX 治疗导致外周血中 CD4+CD25+Foxp3+Treg 和 CD4+CD25-Foxp3+Treg 细胞的相对显著和持续增加（与基线相比，均 P<0.0001），特别是在应答者中（与无应答者相比，均 P<0.05）。CRP 随时间的变化与 CD25+Foxp3+细胞的增加呈负相关（P<0.001，r=-0.39），持久的临床应答与循环 Foxp3+细胞的持续增加相关。令人惊讶的是，IFX 治疗下调了 UC 和 CD 应答者肠道黏膜 Foxp3 的 mRNA 和蛋白表达（均 P<0.001），但在无应答者中无此作用。