Cheluvappa Rajkumar
Department of Medicine, St. George Clinical School, University of New South Wales, Sydney, NSW, Australia,
Int J Colorectal Dis. 2014 Oct;29(10):1181-8. doi: 10.1007/s00384-014-1936-5. Epub 2014 Jul 1.
Crohn's disease and ulcerative colitis are the two spectral variations of inflammatory bowel diseases (IBD). The complex interplay between genetic predisposition, gastrointestinal bacteria, and gut immunity in IBD is yet to be deciphered. The newly described IL-17-secreting subset of CD4+ T cells, called Th17 cells (and its "Th17 system"), has been increasingly implicated in the pathogenesis of inflammatory changes in inflammatory/autoimmune diseases including IBD. The chemokine ligand CCL20 and its receptor CCR6 are both upregulated in colon biopsy samples during active IBD. Appendicitis and appendectomy (AA) prevents or significantly ameliorates human IBD.
We pioneered the first animal model of AA. AA was performed on 5-week-old male BALB/c mice, and distal-colon samples were harvested. Mice with two laparotomies each served as sham and sham (SS) controls. RNA was extracted from individual colonic replicate samples (AA and SS groups) and each sample microarray analyzed and reverse transcription-polymerase chain reaction (RT-PCR) validated. Gene set enrichment analysis (GSEA) software was used to further analyze the microarray data.
Prior AA ameliorates experimental colitis in our murine model. CCL20 expression was significantly suppressed (along with components of the Th17 system) in the most distal colon 3 and 28 days after AA was done at the most proximal colon.
Teasing out the pathways involved in the changes induced by AA on the colon in clinical studies and, most importantly, in our unique murine AA model will lead to the development of techniques to manipulate different components of the CCL20-CCR6 axis and Th17 system resulting in significant advances in IBD management.
克罗恩病和溃疡性结肠炎是炎症性肠病（IBD）的两种光谱变异类型。IBD中遗传易感性、胃肠道细菌和肠道免疫之间复杂的相互作用尚待阐明。新描述的分泌白细胞介素-17的CD4+T细胞亚群，即Th17细胞（及其“Th17系统”），越来越多地被认为与包括IBD在内的炎症性/自身免疫性疾病的炎症变化发病机制有关。趋化因子配体CCL20及其受体CCR6在活动性IBD期间的结肠活检样本中均上调。阑尾炎和阑尾切除术（AA）可预防或显著改善人类IBD。
我们开创了首个AA动物模型。对5周龄雄性BALB/c小鼠进行AA手术，并采集远端结肠样本。每组接受两次剖腹手术的小鼠作为假手术和假手术（SS）对照。从各个结肠重复样本（AA组和SS组）中提取RNA，对每个样本进行微阵列分析并用逆转录-聚合酶链反应（RT-PCR）验证。使用基因集富集分析（GSEA）软件进一步分析微阵列数据。
在我们的小鼠模型中，预先进行的AA可改善实验性结肠炎。在近端结肠进行AA后3天和28天，最远端结肠中的CCL20表达（以及Th17系统的成分）被显著抑制。
在临床研究中，最重要的是在我们独特的小鼠AA模型中，梳理出AA对结肠诱导变化所涉及的途径，将导致开发出操纵CCL20-CCR6轴和Th17系统不同成分的技术，从而在IBD管理方面取得重大进展。
