关键词： Cytokines   Gastroenterology   Immunology   Inflammatory bowel disease   T cells  

摘要： It remains unknown what causes inflammatory bowel disease (IBD), including signaling networks perpetuating chronic gastrointestinal inflammation in Crohn's disease (CD) and ulcerative colitis (UC), in humans. According to an analysis of up to 500 patients with IBD and 100 controls, we report that key transcripts of the IL-7 receptor (IL-7R) pathway are accumulated in inflamed colon tissues of severe CD and UC patients not responding to either immunosuppressive/corticosteroid, anti-TNF, or anti-alpha(4)beta(7) therapies. High expression of both IL7R and IL-7R signaling signature in the colon before treatment is strongly associated with nonresponsiveness to anti-TNF therapy. While in mice IL-7 is known to play a role in systemic inflammation, we found that in humans IL-7 also controlled alpha(4)beta(7) integrin expression and imprinted gut-homing specificity on T cells. IL-7R blockade reduced human T cell homing to the gut and colonic inflammation in vivo in humanized mouse models, and altered effector T cells in colon explants from UC patients grown ex vivo. Our findings show that failure of current treatments for CD and UC is strongly associated with an overexpressed IL-7R signaling pathway and point to IL-7R as a relevant therapeutic target and potential biomarker to fill an unmet need in clinical IBD detection and treatment.

关键词： 肠道干细胞   肠道类器官   肠道疾病   药物测试   再生医学  

摘要： 随着干细胞和组织培养技术的不断发展,由肠道干细胞自我更新、分化、组建形成的3D肠道类器官被成功构建,克服了永生化细胞和动物模型在肠功能和疾病研究中的局限性。3D肠道类器官的成功构建,不仅可用于原生肠道发育研究,而且可用于个体化疾病模型、精准医学和肠疾病特异性药物测试研究。通过成体组织活检或多能干细胞定向诱导分化产生的肠道类器官,重现与在体肠组织相似的黏液产生、吸收和分泌等功能,与荧光标记技术相结合可实现肠渗透性功能的实时观察。根据不同实验目的培育的肠道类器官,不仅可用于构建炎症性肠病、短肠综合征、乳糜泻、憩室病、囊性纤维化、结肠直肠癌、食管腺癌、放射性肠损伤、细菌和病毒感染等肠疾病模型,而且可以对化合物诱导毒性和炎症损伤产生反应,为肠道药物测试提供了新的临床试验模型。