Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
Gastroenterology. 2011 Dec;141(6):2026-38. doi: 10.1053/j.gastro.2011.08.032. Epub 2011 Aug 27.
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).
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.
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 κB 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.
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.
抗肿瘤坏死因子（TNF）抗体英夫利昔单抗、阿达木单抗和培塞利珠单抗已被证实对克罗恩病具有临床疗效。在此，我们评估了抗 TNF 抗体对炎症性肠病（IBD）中细胞凋亡的影响。
从 IBD 患者和对照患者的外周血和黏膜固有层单核细胞中分离 CD14+巨噬细胞和 CD4+T 细胞。通过免疫组织化学和荧光激活细胞分选技术评估细胞表面标志物和细胞凋亡。
IBD 患者的黏膜固有层 CD14+巨噬细胞比 CD4+T 细胞表现出更高频率和更高水平的膜结合 TNF（mTNF）表达，而 IBD 黏膜 CD4+T 细胞中诱导了 TNF 受体（TNFR）2、TNF 受体相关因子（TRAF）2 和核因子κB 等 mTNF 依赖性信号蛋白。大多数抗 TNF 抗体在纯化的外周或黏膜 CD4+T 细胞中均不会诱导 T 细胞凋亡。然而，与依那西普不同，当表达 TNFR2+的黏膜固有层 CD4+T 细胞与 mTNF+CD14+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，在对照患者中未观察到这些作用。在 IBD 患者中，接受阿达木单抗和英夫利昔单抗治疗后会发生 T 细胞凋亡，这种凋亡严重依赖于 TNFR2 信号转导，可通过白细胞介素 6 信号转导来预防。阻断白细胞介素 6R 信号转导可增强 IBD 中抗 TNF 诱导的 T 细胞凋亡。
只有当黏膜 TNFR2+T 细胞与表达 mTNF 的 CD14+巨噬细胞共培养时，临床有效的抗 TNF 抗体才能在 IBD 中诱导 T 细胞凋亡。抗 TNF 抗体通过靶向 mTNF/TNFR2 途径间接诱导细胞凋亡的发现，可能对 IBD 新治疗策略的发展具有重要意义。
