Treatment of murine Th1-and Th2-mediated inflammatory bowel disease with NF-κB decoy oligonucleotides
Treatment of murine Th1-and Th2-mediated inflammatory bowel disease with NF-κB decoy oligonucleotides
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DOI：
10.1172/jci24792
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发表时间：
2005-11-01
影响因子：
15.9
通讯作者：
Kitani, A
中科院分区：
文献类型：
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作者：
Fichtner-Feigl, S;Fuss, IJ;Kitani, A
Th 1和Th 2 T细胞应答是炎症性肠病（IBD）的基础，可能依赖于NF-κ B转录活性。我们在确定NF-κ B诱饵寡脱氧核苷酸（诱饵ODN）治疗各种IBD小鼠模型的能力的研究中探索了这种可能性。在最初的研究中，我们发现i.r.（直肠内）或腹膜内施用包封在病毒包膜中的诱饵ODN预防和治疗急性三硝基苯磺酸诱导的（TNBS诱导的）结肠炎模型，如通过临床过程和对Th 1细胞因子产生的影响所评估的。在进一步的研究中，我们表明NF-κ B诱饵ODN也是慢性TNBS结肠炎模型的有效治疗，抑制IL-23/IL-17的产生和表征该模型的纤维化的发展。通过i.r.给予NF-κ B诱饵ODNs不抑制肠外器官中的NF-κ B，并导致CD 4（+）T细胞凋亡，表明这种治疗是高度集中和持久的。最后，我们发现NF-κ B诱饵ODNs也预防和治疗恶唑酮结肠炎，从而影响Th 2介导的炎症过程。在每种情况下，诱饵给药导致炎症清除作用，表明适用于人IBD的治疗效力。的
The Th1 and Th2 T cell responses that underlie inflammatory bowel diseases (IBDs) are likely to depend on NF-kappa B transcriptional activity. We explored this possibility in studies in which we determined the capacity of NF-kappa B decoy oligodeoxynucleotides (decoy ODNs) to treat various murine models of IBD. In initial studies, we showed that i.r. (intrarectal) or i.p. administration of decoy ODNs encapsulated in a viral envelope prevented and treated a model of acute trinitrobenzene sulfonic acid-induced (TNBS-induced) colitis, as assessed by clinical course and effect on Th1 cytokine production. In further studies, we showed that NF-kappa B decoy ODNs were also an effective treatment of a model of chronic TNBS-colitis, inhibiting both the production of IL-23/IL-17 and the development of fibrosis that characterizes this model. Treatment of TNBS-induced inflammation by i.r. administration of NF-kappa B decoy ODNs did not inhibit NF-kappa B in extraintestinal organs and resulted in CD4(+) T cell apoptosis, suggesting that such treatment is highly focused and durable. Finally, we showed that NF-kappa B decoy ODNs also prevented and treated oxazolone-colitis and thus affect a Th2-mediated inflammatory process. In each case, decoy administration led to inflammation-clearing effects, suggesting a therapeutic potency applicable to human IBD. OF