Brasseit J, Althaus-Steiner E, Faderl M, Dickgreber N, Saurer L, Genitsch V, Dolowschiak T, Li H, Finke D, Hardt W-D, McCoy K D, Macpherson A J, Corazza N, Noti M, Mueller C
Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
Division of Clinical Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
Mucosal Immunol. 2016 May;9(3):689-701. doi: 10.1038/mi.2015.93. Epub 2015 Sep 16.
Current therapies to treat inflammatory bowel diseases have limited efficacy, significant side effects, and often wane over time. Little is known about the cellular and molecular mechanisms operative in the process of mucosal healing from colitis. To study such events, we developed a new model of reversible colitis in which adoptive transfer of CD4(+)CD45RB(hi) T cells into Helicobacter typhlonius-colonized lymphopenic mice resulted in a rapid onset of colonic inflammation that was reversible through depletion of colitogenic T cells. Remission was associated with an improved clinical and histopathological score, reduced immune cell infiltration to the intestinal mucosa, altered intestinal gene expression profiles, regeneration of the colonic mucus layer, and the restoration of epithelial barrier integrity. Notably, colitogenic T cells were not only critical for induction of colitis but also for maintenance of disease. Depletion of colitogenic T cells resulted in a rapid drop in tumor necrosis factor α (TNFα) levels associated with reduced infiltration of inflammatory immune cells to sites of inflammation. Although neutralization of TNFα prevented the onset of colitis, anti-TNFα treatment of mice with established disease failed to resolve colonic inflammation. Collectively, this new model of reversible colitis provides an important research tool to study the dynamics of mucosal healing in chronic intestinal remitting-relapsing disorders.
目前用于治疗炎症性肠病的疗法疗效有限、副作用显著，且往往会随着时间的推移而减弱。关于结肠炎黏膜愈合过程中起作用的细胞和分子机制，我们了解得还很少。为了研究此类事件，我们开发了一种新的可逆性结肠炎模型，将CD4(+)CD45RB(hi) T细胞过继转移到定殖有盲肠弯曲杆菌的淋巴细胞减少的小鼠体内，会导致结肠炎症迅速发作，而通过清除致结肠炎T细胞，炎症是可逆的。缓解与临床和组织病理学评分的改善、免疫细胞向肠黏膜浸润的减少、肠道基因表达谱的改变、结肠黏液层的再生以及上皮屏障完整性的恢复有关。值得注意的是，致结肠炎T细胞不仅对结肠炎的诱导至关重要，而且对疾病的维持也很关键。清除致结肠炎T细胞会导致肿瘤坏死因子α（TNFα）水平迅速下降，这与炎症免疫细胞向炎症部位浸润的减少有关。虽然中和TNFα可预防结肠炎的发作，但对已患疾病的小鼠进行抗TNFα治疗未能消除结肠炎症。总的来说，这种新的可逆性结肠炎模型为研究慢性肠道缓解-复发疾病中黏膜愈合的动态过程提供了一个重要的研究工具。
