Comparative analysis of the effects of anti‐IL‐6 receptor mAb and anti‐TNF mAb treatment on CD4+ T‐cell responses in murine colitis
Comparative analysis of the effects of anti‐IL‐6 receptor mAb and anti‐TNF mAb treatment on CD4+ T‐cell responses in murine colitis
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DOI：
10.1002/ibd.21384
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发表时间：
2011-02
影响因子：
4.9
通讯作者：
F. Terabe;M. Fujimoto;S. Serada;S. Shinzaki;H. Iijima;M. Tsujii;N. Hayashi;S. Nomura;H. Kawahata;M. Jang;M. Miyasaka;M. Mihara;Y. Ohsugi;T. Kishimoto;T. Naka
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作者：
F. Terabe;M. Fujimoto;S. Serada;S. Shinzaki;H. Iijima;M. Tsujii;N. Hayashi;S. Nomura;H. Kawahata;M. Jang;M. Miyasaka;M. Mihara;Y. Ohsugi;T. Kishimoto;T. Naka
背景：抗肿瘤坏死因子单克隆抗体（anti - TNF - mAb）治疗克罗恩病（CD）的疗效已经得到证实，抗白细胞介素- 6受体（anti - IL - 6R） mAb也被报道对CD有效。然而，目前尚不清楚这两种药物在CD治疗中的疗效和机制是否不同。方法：采用过继性转移性结肠炎模型，我们比较了抗IL - 6R单抗、抗TNF单抗和TNF受体- Fc融合蛋白（TNFR - Fc）对CD4+ T细胞的疗效及其作用方式。我们还使用相同的模型研究了Th1和Th17细胞在结肠炎中的作用。结果：抗IL - 6R单抗组和抗TNF单抗组的组织学评分明显低于对照组，而TNF - Fc组的组织学评分则明显低于对照组，其中抗IL - 6R单抗组的评分最低。在抗IL - 6R单抗组和抗TNF单抗组中，增殖CD4+ T细胞的频率降低，但在TNFR - Fc组中没有，而CD4+ T细胞凋亡的频率在所有组中相似。抗IL - 6R单抗抑制Th17细胞的诱导，增加固有层调节性T细胞的频率，而抗TNF单抗对CD4+ T细胞分化没有影响。CD4+ T细胞中干扰素γ和/或IL - 17的缺乏降低了结肠炎的严重程度。结论：我们的研究结果表明，抑制致病性CD4+ T细胞的增殖是生物制剂治疗结肠炎的主要作用方式。抗IL - 6R单抗可能对Th17显性和Treg频率受损的CD患者有益处。（炎症肠病2011）
Background: The efficacy of anti‐tumor necrosis factor monoclonal antibody (anti‐TNF mAb) for Crohn's disease (CD) is well established, and anti‐interleukin‐6 receptor (anti‐IL‐6R) mAb has also been reported to be effective in CD. It is, however, unclear if the efficacy and mechanisms of both agents are different in CD therapy. Methods: Using an adoptive transfer colitis model, we compared the efficacy of anti‐IL‐6R mAb, anti‐TNF mAb, and TNF receptor‐Fc fusion protein (TNFR‐Fc), and their modes of action on CD4+ T cells. We also investigated the role of Th1 and Th17 cells in colitis using the same model. Results: The histological scores for the anti‐IL‐6R mAb and anti‐TNF mAb groups but not for TNFR‐Fc group were much lower than that for the control group, and the score was the lowest for the anti‐IL‐6R mAb group. The frequency of proliferating CD4+ T cells was reduced in anti‐IL‐6R mAb and anti‐TNF mAb groups, but not in the TNFR‐Fc group, whereas the frequency of apoptotic CD4+ T cells was similar in all groups. Anti‐IL‐6R mAb suppressed the induction of Th17 cells and increased the frequency of lamina propria regulatory T cells, whereas anti‐TNF mAb exerted no influence on CD4+ T‐cell differentiation. A deficiency in interferon‐γ and/or IL‐17 in CD4+ T cells reduced the severity of colitis. Conclusions: Our findings suggest that suppression of the proliferation of pathogenic CD4+ T cells is the major mode of action of biological agents for colitis therapy. Anti‐IL‐6R mAb might have benefits in CD patients with Th17 dominance and impaired Treg frequency. (Inflamm Bowel Dis 2011)