Antibodies Against Tumor Necrosis Factor (TNF) Induce T-Cell Apoptosis in Patients With Inflammatory Bowel Diseases via TNF Receptor 2 and Intestinal CD14+ Macrophages
Antibodies Against Tumor Necrosis Factor (TNF) Induce T-Cell Apoptosis in Patients With Inflammatory Bowel Diseases via TNF Receptor 2 and Intestinal CD14+ Macrophages
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DOI：
10.1053/j.gastro.2011.08.032
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发表时间：
2011-12-01
期刊：
影响因子：
29.4
通讯作者：
Neurath, Markus F.
中科院分区：
文献类型：
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作者：
Atreya, Raja;Zimmer, Michael;Neurath, Markus F.
背景与目的：抗肿瘤坏死因子（TNF）抗体英夫利西单抗、阿达木单抗和赛妥珠单抗已被证明在克罗恩病中具有临床疗效。在这里，我们评估了抗TNF抗体对炎症性肠病（IBD）细胞凋亡的影响。方法：采用正交设计法从IBD患者和对照患者的外周血和固有层单核细胞中分离出CD 14（+）巨噬细胞和CD 4（+）T细胞。细胞表面标志物和凋亡进行了评估，免疫组织学和荧光激活细胞分选技术。研究结果：IBD患者固有层CD 14（+）巨噬细胞比CD 4（+）T细胞表现出更频繁和更高的膜结合TNF（mTNF）表达，而mTNF依赖性信号蛋白如TNF受体（TNFR）2、TNFR相关因子（TRAF）2和核因子κ B在IBD粘膜CD 4（+）T细胞中被诱导。大多数抗TNF抗体在纯化的外周或粘膜CD 4（+）T细胞中不诱导T细胞凋亡。然而，与依那西普相反，当表达TNFR 2（+）的固有层CD 4（+）T细胞与mTNF（+）CD 14（+）肠巨噬细胞共培养时，所有临床有效的抗TNF抗体均可显著诱导IBD中的T细胞凋亡。相比之下，在对照组患者中没有观察到任何影响。IBD中的T细胞凋亡在阿达木单抗和英夫利昔单抗治疗后在体内发生，严重依赖于TNFR 2信号传导，并且可以通过白细胞介素-6信号转导来预防。在IBD中阻断白细胞介素-6R信号增强抗TNF诱导的T细胞凋亡。结论：只有当粘膜TNFR 2（+）T细胞与表达mTNF的CD 14（+）巨噬细胞共培养时，临床有效的抗TNF抗体才能诱导IBD中的T细胞凋亡。抗TNF抗体通过靶向mTNF/TNFR 2途径间接诱导细胞凋亡的发现可能对IBD新治疗策略的开发具有重要意义。
BACKGROUND & AIMS: The anti-tumor necrosis factor (TNF) antibodies infliximab, adalimumab, and certolizumab pegol have proven clinical efficacy in Crohn's disease. Here, we assessed the effects of anti-TNF antibodies on apoptosis in inflammatory bowel disease (IBD). METHODS: CD14(+) macrophages and CD4(+) T cells were isolated from peripheral blood and lamina propria mononuclear cells from patients with IBD and control patients. Cell surface markers and apoptosis were assessed by immunohistology and fluorescence-activated cell sorting techniques. RESULTS: Lamina propria CD14(+) macrophages showed significantly more frequent and higher membrane-bound TNF (mTNF) expression than CD4(+) T cells in IBD, whereas mTNF-dependent signaling proteins such as TNF receptor (TNFR) 2, TNFR-associated factor (TRAF) 2, and nuclear factor kappa B were induced in IBD mucosal CD4(+) T cells. Most anti-TNF antibodies did not induce T-cell apoptosis in purified peripheral or mucosal CD4(+) T cells. However, in contrast to etanercept, administration of all clinically effective anti-TNF antibodies resulted in a significant induction of T-cell apoptosis in IBD when lamina propria CD4(+) T cells expressing TNFR2(+) were cocultured with mTNF(+) CD14(+) intestinal macrophages. In contrast, no effects in control patients were noted. T-cell apoptosis in IBD occurred in vivo after treatment with adalimumab and infliximab, was critically dependent on TNFR2 signaling, and could be prevented via interleukin-6 signal transduction. Blockade of interleukin-6R signaling augmented anti-TNF-induced T-cell apoptosis in IBD. CONCLUSIONS: Clinically effective anti-TNF antibodies are able to induce T-cell apoptosis in IBD only when mucosal TNFR2(+) T cells are cocultured with mTNF-expressing CD14(+) macrophages. The finding that anti-TNF antibodies induce apoptosis indirectly by targeting the mTNF/TNFR2 pathway may have important implications for the development of new therapeutic strategies in IBD.