A Novel Model of Inflammatory Bowel Disease: Mice Deficient for the Multiple Drug Resistance Gene,mdr1a, Spontaneously Develop Colitis

Abstract

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.

Methods of Inducing Inflammatory Bowel Disease in Mice

“…The multiple drug resistance 1a (mdr1a) gene codes for an ATP-binding cassette transporter that is thought to play a role in pumping molecules out of cells (Schinkel et al, 1994). Mice deÞcient in the mdr1a gene develop spontaneous colitis around age 12 to 15 weeks (Panwala et al, 1998), with the penetrance and severity being quite variable depending on the cleanliness of the institutional animal facility. The timing can be greatly accelerated and frequency of disease can be increased by infecting the genetically modi-Þed mice via oral gavage with Helicobacter bilis, an enteric bacterium which is endemic in many mouse colonies, but causes no overt pathology in control mice (Maggio-Price et al, 2002).…”

“…The reasons for spontaneous colitis in the mdr1a −/− mice are unclear. Chimeric reconstitution experiments indicate that a defect in the non-hematopoietic compartment, such as the gut epithelium, confers susceptibility to colitis (Panwala et al, 1998). The inability of the gut epithelium to pump bacterial antigens back out into the gut lumen probably results in increased antigen presentation and subsequent priming of the immune system to native ßora (Wilk et al, 2005).…”

Overview of Mouse Models of Inflammatory Bowel Disease and Their Use in Drug Discovery

“…Mdr1a −/− mice on an FVB background spontaneously develop IBD when housed under SPF conditions (Panwala et al, 1998). Typically, disease onset is not synchronous, occurring between 8 and 36 weeks of age, with a penetrance of ∼20% to 25%.…”

“…Antibiotic treatment of mdr1a −/− mice, either prophylactically or therapeutically, prevents the disorder, suggesting a crucial involvement of bacteria in driving IBD (Panwala et al, 1998). Oral infection of mdr1a −/− mice with H. bilis greatly facilitates onset and penetrance of the condition as compared to uninfected mice, with up to 90% penetrance by 16 weeks (UNIT 5.58;Maggio-Price et al, 2002).…”

“…Histological analysis reveals inflammation primarily in the large intestine and cecum (Panwala et al, ). The condition most closely resembles human ulcerative colitis, as inflammation is present throughout the colon and is marked by mucosal thickening, loss of goblet cells, crypt abscesses, and ulceration.…”