Development of novel mouse model of human Crohn's disease

炎症性肠病(IBD)是一种慢性胃肠道炎症，在日本的患病率一直在上升。然而，尽管进行了广泛的病理生理研究，但由于IBD的病因仍不清楚，因此还没有建立起基本的治疗方法。近年来对IBD病理生理状况的研究进展为免疫系统调节剂作为治疗工具提供了新的手段。葡聚糖硫酸钠(DSS)诱导的结肠炎、白介素10缺陷(IL-10-/-)小鼠、CD4^+CD45^&lt；RBHigh&gt；转移模型等动物模型已被广泛应用于肠道炎症的研究和新药疗效的检测。首先，我们将NOD-SCID小鼠与IL-2Rγc基因敲除小鼠杂交，获得了完全缺乏免疫细胞的NOD/SCID×IL-2RγCko(NOG)小鼠，是移植实验的理想受体。我们已经为本研究建立了稳定的NOG小鼠来源。接下来，我们利用人类菌群相关(HFA)小鼠研究了肠道微叶在肠道炎症中的重要性。菌群分析结果表明，HFA小鼠模型可复制溃疡性结肠炎(UC)小鼠肠道菌群紊乱。然而，给野生型小鼠灌胃UC菌群不会引起肠道炎症。相比之下，在DSS给药后，与定居在健康对照(HC)菌群中的小鼠相比，UC菌群定植的小鼠表现出严重的炎症。此外，在IL-10-/-小鼠中，UC flora小鼠的几个炎症参数也比HC flora小鼠严重。这些结果表明，肠道细菌平衡的破坏增加了肠道炎症刺激的易感性。

Inflammatory bowel disease(IBD) is a chronic inflammation of the gastrointestinal tract and its prevalence has been increasing in Japan. However, no fundamental therapy has been established because the etiology of IBD remains obscure in spite of extensive pathophysiological researches. Recent advances in the understanding of the pathophysiological conditions of IBD have provided new immune system modulators as therapeutic tools. Animal models, such as dextran sulfate sodium(DSS)-indeced colitis, interleukin-10 deficient(IL-10-/-) mice and CD4^+CD45^<RBhigh> transfer model, have been widely used for studying the intestinal inflammation and testing therapeutic effect of newly-developed drugs. However, there has not been established ideal animal models resembling the pathogenesis of human IBD including intestinal microflora which plays an important role for inducing and perpetuating the intestinal inflammation.At First, we crossed NOD-SCID mice with IL-2Rγc knock out mice and obtained NOD/SCID×IL-2RγcKO(NOG) mice which completely deficient immnocompetent cells and is ideal for the recipient of transplant experiment. We already established stable supply of the NOG mice for the present study.Next, we studied the importance of intestinal microfolora in the intestinal inflammation using human flora associated(HFA) mice. Results of flora analysis indicated that derangement of intestinal flora with ulcerative colitis(UC) was reproduced in HFA mice model. However, intestinal inflammation was not induced by administration of UC flora in wild-type mice. In contrast, mice colonized with UC flora presented severe inflammation compared with mice colonized with healthy control(HC) flora upon DSS administration. Moreover, in IL-10-/- mice, several inflammatory parameters were also severer in UC flora mice than those in HC flora mice. These results suggested that breakdown of intestinal bacterial balance increased the susceptibility of intestinal inflammatory stimuli.