Related Experiment Videos
A novel model of inflammatory bowel disease: mice deficient for the multiple drug resistance gene, mdr1a,
C M Panwala1, J C Jones, J L Viney
1Department of Molecular Immunology, Immunex Corporation, Seattle, WA 98101, USA.
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.
Insights
Mice lacking the mdr1a gene spontaneously develop intestinal inflammation resembling human inflammatory bowel disease (IBD). Antibiotic treatment prevents and resolves this colitis, suggesting a role for gut bacteria in IBD pathogenesis.
Area of Science:
- Immunology
- Gastroenterology
- Genetics
Background:
- The murine multiple drug resistance (mdr) gene, mdr1a, encodes a transmembrane protein expressed in various tissues, including the intestine.
- Mdr1a protein plays a role in cellular transport and protection.
Purpose of the Study:
- To investigate the physiological role of mdr1a in the absence of its gene product.
- To characterize spontaneous intestinal inflammation in mdr1a knockout mice.
- To explore the potential link between mdr1a deficiency, gut microbiota, and inflammatory bowel disease (IBD).
Main Methods:
- Generation of mdr1a knockout (mdr1a-/-) mice.
- Maintenance of mice under specific pathogen-free conditions.
- Histopathological analysis of intestinal tissue.
- Assessment of immune cell reactivity to bacterial antigens.
- Evaluation of antibiotic treatment efficacy.
Main Results:
- mdr1a-/- mice spontaneously develop severe intestinal inflammation with pathology similar to human IBD.
- Inflammation is characterized by dysregulated epithelial cell growth and leukocytic infiltration.
- Oral antibiotic treatment prevents disease onset and resolves active colitis.
- Lymphoid cells from affected mice show functional reactivity to intestinal bacterial antigens.
Conclusions:
- This study presents the first description of spontaneous colitis in a gene knockout mouse with an intact immune system.
- The mdr1a-/- mouse is a novel model for studying IBD pathogenesis, immune reactivity to gut bacteria, and the role of mdr genes in the colonic microenvironment.
- Findings suggest a critical role for the gut microbiota in the development of spontaneous colitis in mdr1a deficient mice.