Contract Research – Inflammatory Bowel Disease Models
Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disorder. It is characterized by mucosal inflammation, epithelial cell destruction and ulceration of the intestinal mucosa, accompanied by weight loss and diarrhea.
Ulcerative colitis and Crohn's disease are two major types of inflammatory bowel disease. Crohn's disease is considered a Th1-dominated disease, but Th-17 contribution to the disease has been suggested as well. Ulcerative colitis is considered a Th2-dominated disease.
There are multiple mouse models of IBD:
- Dextran sulfate sodium (DSS)-induced colitis
- TNBS-induced colitis
- Oxazolone-induced colitis
- CD4+CD45RBhigh cell transfer into SCID mice
- Spontaneous IBD in some transgenic mice (primarily IL-2-, IL-10- and MDR1a-deficient mice)
Hooke Laboratories offers multiple models of IBD and is continuously evaluating new models.
DSS-Induced Colitis
Oral administration of dextran sulfate sodium (DSS) in drinking water for 5 to 7 days induces IBD-like disease in mice. After the removal of DSS from drinking water, mice slowly recover (BALB/c mice) or develop chronic colitis (C57BL/6 mice). This is a model of Crohn's disease.
Drug effects can be evaluated during various periods of disease induction. T- and B-lymphocytes are not necessary for induction of colitis in this model because disease develops also in RAG-1 deficient mice. However, it is possible that T- and B-lymphocytes contribute to disease severity in milder forms of DSS-induced colitis when lower concentrations of DSS are used in drinking water.
In this model:
- IL-12p35 KO mice are protected
- Anti-TNF therapy efficacy is not clear, mixed results reported
- IL-18 KO have worse disease (but anti-IL-18 antibodies may provide benefit)
- Anti-IL-17 makes colitis worse
TNBS-Induced Colitis
Intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) leads to development of inflammation limited to the colon and dominated by a strong Th1-type immune response. The peak of clinical disease is at 2 to 4 weeks after TNBS administration. Clinical signs of colitis subside about 2 months after TNBS administration. The severity of disease can be significantly reduced by injecting blocking anti-p40IL-12/IL-23 antibodies into the mice as late as 20 days after TNBS administration. This is a model of Crohn's disease. Drug effects can be evaluated during various periods of disease induction.
In this model:
- IL-17R KO mice have reduced colitis
- IL-23 KO mice develop worse colitis
- (and anti-p40 antibodies reduce disease severity, indicating that IL-12, but not IL-23, plays a critical pathogenic role)
- TNF blockade appears to reduce disease severity
- IFNγ blockade (or IFNγR KO mice) does not alter colitis
Oxazolone-Induced Colitis
Intrarectal administration of oxazolone leads to development of inflammation limited to the distal half of the colon and dominated by a Th2-type immune response. The disease can be prevented by injecting anti-IL-4 antibodies into the mice at the time of oxazolone administration. This is a model of ulcerative colitis. Drug effects can be evaluated during various periods of disease induction.
In this model:
- TNF blockade does not reduce disease severity
- FTY720 is effective in reducing disease severity
- Anti-IL-4 antibodies prevent disease development
CD4+CD45RBhigh Cell Transfer into SCID Mice
This is a relatively long model (8-12 weeks) where SCID mice develop colitis after transfer of CD4+CD45RBhigh cell from normal mice. The transferred population has a greatly reduced number of regulatory T cells and the recipient mice develop autoimmune colitis. If the recipient mice are kept under very clean conditions (sterile food, water, bedding), fewer mice will develop colitis. Under these clean conditions, the recipient mice will develop skin disease having some resemblance to psoriasis.
Th1-type cytokines appear to play an important role in this model, as in Crohn's disease. It is therefore considered a good model of Crohn's disease.
In this model:
- TNF blockade partially blocks colitis development (not if applied only during the first 3 weeks after cell transfer)
- IL-12 blockade (anti-p40) reduces disease severity
- IFNγ blockade reduces disease severity
- IL-10 administration completely blocks disease
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