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，尽管有广泛的病理生理学研究，但IBD的病因仍然不清楚，因此尚未建立基本的治疗方法。对IBD的病理生理学状况的理解的最新进展提供了新的免疫系统调节剂作为治疗工具。动物模型如葡聚糖硫酸钠（DSS）诱导的结肠炎、白细胞介素-10（IL-10）缺陷小鼠和CD 4 ^+ CD 45 ^<RBhigh>转移模型已广泛用于研究肠道炎症和检测新药的疗效。本研究首先将NOD-SCID小鼠与IL-2 R γc基因敲除小鼠杂交，获得了免疫活性细胞完全缺失的NOD/SCID×IL-2 R γcKO（NOG）小鼠，并对NOD/SCID×IL-2 R γcKO（NOG）小鼠的免疫活性进行了研究。我们已经为本研究建立了稳定的NOG小鼠供应。接下来，我们使用人类植物群相关（HFA）小鼠研究了肠道微生物群在肠道炎症中的重要性。植物群分析结果表明，HFA小鼠模型可复制溃疡性结肠炎（UC）时肠道植物群紊乱。然而，在野生型小鼠中给予UC植物群不会诱导肠道炎症。相比之下，在DSS施用后，与用健康对照（HC）植物群定殖的小鼠相比，用UC植物群定殖的小鼠呈现严重的炎症。此外，在IL-10-/-小鼠中，UC植物群小鼠中的几个炎症参数也比HC植物群小鼠中的炎症参数更严重。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.