Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice
Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice
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DOI：
10.1053/j.gastro.2007.03.104
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发表时间：
2007-06-01
期刊：
影响因子：
29.4
通讯作者：
Kastelein, Robert A.
中科院分区：
文献类型：
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作者：
Elson, Charles O.;Cong, Yingzi;Kastelein, Robert A.
背景与目的：白细胞介素（IL）-23支持产生IL-17（Th17）的T细胞的独特谱系，其可以介导慢性炎症。本研究旨在确定IL-23和Th17细胞在小鼠慢性结肠炎中的作用。方法：通过将盲肠细菌抗原特异性C3H/HeJBir（C3Bir）CD4（+）T细胞系转移至C3H/HeSnJ SCID小鼠来诱导结肠炎。流式细胞术，酶联免疫吸附试验，实时聚合酶链反应测定细胞因子。单克隆抗IL-23 p19在致病性CD4 T细胞转移的同时或4周后给药。以设盲方式评估组织病理学结肠炎评分。结果如下：致病性C3 Bir CD 4 + T细胞细颗粒含有比产生干扰素γ的细胞更多的产生IL-17的细胞，并且这些是不同的亚群;过继转移到SCID受体后，Th 17细胞在固有层中占主导地位。患结肠炎的老鼠产生细菌反应性CD4（+）Th1和Th17细胞系。Th17细胞以剂量依赖性方式诱导显著的炎症。即使在低至10（4）个细胞/小鼠的剂量下，Th17细胞诱导的疾病也比Th1细胞在10（6）个细胞/小鼠下诱导的疾病更严重。单克隆抗IL-23 p19预防和治疗活动性结肠炎，下调结肠中广泛的炎性细胞因子和趋化因子。抗IL-23 p19在体内外诱导大肠杆菌Th17细胞凋亡。结论：细菌反应性CD4 + Th17细胞是慢性结肠炎的有效效应细胞。抑制IL-23 p19对预防和治疗活动性结肠炎均有效。IL-23是炎症性肠病的有吸引力的治疗靶点。
Background & Aims: Interleukin (IL)-23 supports a distinct lineage of T cells producing IL-17 (Th17) that can mediate chronic inflammation. This study was performed to define the role of IL-23 and Th17 cells in chronic colitis in mice. Methods: Colitis was induced by transfer of a cecal bacterial antigen-specific C3H/HeJBir (C3Bir) CD4(+) T-cell line to C3H/HeSnJ SCID mice. Cytokines were measured by flow cytometry, enzyme-linked immunosorbent assay, and realtime polymerase chain reaction. Monoclonal anti-IL-23p19 was administered at the same time as or 4 weeks after pathogenic CD4 T-cell transfer. A histopathology colitis score was assessed in a blinded fashion. Results: The pathogenic C3Bir CD4+ T-cell fine contained more cells producing IL-17 than those producing interferon-gamma and these were distinct subsets; after adoptive transfer to SCID recipients, Th17 cells were predominant in the lamina propria. of mice with colitis. Bacteria-reactive CD4(+) Th1 and Th17 lines were generated. The Th17 cells induced marked inflammation in a dose-dependent manner. Even at a dose as low as 10(4) cells/mouse, Th17 cells induced more severe disease than Th1 cells did at 10(6) cells/mouse. Monoclonal anti-IL-23p19 prevented and treated active colitis, with down-regulation of a broad array of inflammatory cytokines and chemokines in the colon. Anti-IL-23p19 induced apoptosis in colitogenic Th17 cells in vitro and in vivo. Conclusions: Bacterial-reactive CD4+ Th17 cells are potent effector cells in chronic colitis. Inhibition of IL-23p19 was effective in both prevention and treatment of active colitis. IL-23 is an attractive therapeutic target for inflammatory bowel disease.