A novel model of inflammatory bowel disease: mice deficient for the multiple drug resistance gene, mdr1a, spontaneously develop colitis.
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.
Panwala
C M
CM
Department of Molecular Immunology, Immunex Corporation, Seattle, WA 98101, USA.
Jones
J C
JC
Viney
J L
JL
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000942:Antigens, Bacterial / Q000276:immunology; D003106:Colon / Q000276:immunology / Q000382:microbiology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D019450:Genes, MDR / Q000276:immunology; D007136:Immunoglobulins / Q000096:biosynthesis / Q000097:blood; D015994:Incidence; D015212:Inflammatory Bowel Diseases / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D007413:Intestinal Mucosa / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008221:Lymphoid Tissue / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000900:Anti-Bacterial Agents; D000942:Antigens, Bacterial; D007136:Immunoglobulins