Panwala C M, Jones J C, Viney J L
Department of Molecular Immunology, Immunex Corporation, Seattle, WA 98101, USA.
J Immunol. 1998 Nov 15;161(10):5733-44.
The murine multiple drug resistance (mdr) gene, mdr1a, encodes a 170-kDa transmembrane protein that is expressed in many tissues including intestinal epithelial cells, a subset of lymphoid cells and hematopoietic cells. We report that mdr1a knockout (mdr1a-/-) mice are susceptible to developing a severe, spontaneous intestinal inflammation when maintained under specific pathogen-free animal facility conditions. The intestinal inflammation seen in mdr1a-/- mice has a pathology similar to that of human inflammatory bowel disease (IBD) and is defined by dysregulated epithelial cell growth and leukocytic infiltration into the lamina propria of the large intestine. Treating mdr1a-/- mice with oral antibiotics can both prevent the development of disease and resolve active inflammation. Lymphoid cells isolated from mice with active colitis are functionally reactive to intestinal bacterial Ags, providing evidence that there is enhanced immunologic responsiveness to the normal bacterial flora during IBD. This study is the first description of spontaneous colitis in a gene knockout mouse with an apparently intact immune system. This novel model of spontaneous colitis may provide new insight into the pathogenesis of IBD, the nature of dysregulated immune reactivity to intestinal bacterial Ags, and the potential functional role of mdr genes expressed in the cells and tissues of the colonic microenvironment.
小鼠多药耐药（mdr）基因mdr1a编码一种170 kDa的跨膜蛋白，该蛋白在包括肠上皮细胞、部分淋巴细胞和造血细胞在内的许多组织中表达。我们报道，在无特定病原体动物设施条件下饲养时，mdr1a基因敲除（mdr1a-/-）小鼠易发生严重的自发性肠道炎症。mdr1a-/-小鼠出现的肠道炎症与人类炎症性肠病（IBD）的病理相似，其特征为上皮细胞生长失调以及白细胞浸润至大肠固有层。用口服抗生素治疗mdr1a-/-小鼠既能预防疾病的发生，又能缓解活动性炎症。从患有活动性结肠炎的小鼠中分离出的淋巴细胞对肠道细菌抗原具有功能性反应，这表明在IBD期间对正常肠道菌群的免疫反应性增强。本研究首次描述了免疫系统看似完整的基因敲除小鼠中的自发性结肠炎。这种新型的自发性结肠炎模型可能为IBD的发病机制、对肠道细菌抗原的免疫反应失调的本质以及在结肠微环境的细胞和组织中表达的mdr基因的潜在功能作用提供新的见解。
