Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic relapsing inflammation of unknown etiology that presents as two main conditions: Crohn’s disease (CD), a transmural granulomatous inflammation involving segments of the small and large intestine, and ulcerative colitis (UC), which mostly affects the mucosal layer of the large intestine or colon1.

Historically, most animal models of IBD have been chemically induced using agents such as dextran sulfate sodium (DSS), 2,4,6-Trinitrobenzenesulfonic acid (TNBS) or oxazolone. Of these, the DSS model, which initiates a lethal inflammatory bowel disease that resembles human ulcerative colitis, is one of the most commonly used. More recently, models of mouse IBD have been developed using naturally occurring mutant mouse strains (e.g. C3H/HeBir), gene-knockout, and transgenic strains that spontaneously develop colitis. Additionally, intestinal inflammation with characteristics resembling both UC and CD has been shown to occur in immunodeficient mice that are reconstituted with a subset of CD4+ T cells1. The adoptive T-cell transfer model has proven to be a highly reproducible and easily manipulated model of colitis2.

The mechanisms underlying the development of IBD are not well understood. Traditionally, it was believed to be an infectious disease; however, the failure to find a causative microbe and the effectiveness of steroid therapy led to the view that IBD may be an immunological or autoimmune disorder. Recent research has suggested that genetic susceptibility and an emerging mucosal immune response against gut constituents are important factors, and that T cells and tumor necrosis factor alpha (TNF-a) play crucial roles in the pathogenesis of the disease1.

Although animal models of IBD are not perfect analogs of the human disease, mouse models have characteristics that closely resemble both UC and CD in humans. The DSS model has similarities to UC and is characterized by colonic epithelial cell lesions and acute inflammation followed by chronic colitis once DSS administration has been terminated. Clinical symptoms include diarrhea and bloody stool1. The adoptive T-cell transfer model has characteristics of UC (like, a diffuse distribution of lesions in the large intestine, crypt elongation and branching, and extensive mucin depletion) as well as CD (like, transmural inflammation, and the presence of many macrophages and lymphocytes with the occasional multinucleated giant cell). Clinical symptoms associated with the adoptive T-cell transfer model include progressive weight loss and loose stool with mucus, but not diarrhea or bloody stool2.

Conventional treatments for IBD include corticosteroids and 5-aminosalicylic acid derivatives, which are not effective in inducing clinical remission and which can have deleterious side effects. Antibody therapies, including anti-TNF-a, anti-IL-12, and anti-IFN-g antibody therapies, have been shown to be effective in the treatment of IBD although repeated systemic antibody administration may also pose potential complications. Novel approaches using gene therapy have also shown some success.

REFERENCES

  1. Boismenu R, and Chen Y. Insights from mouse models of colitis. J Leukoc Biol, 2000;67(3):267–278.
  2. Read S, and Powrie F. Induction of Inflammatory Bowel Disease in Immunodeficient Mice by Depletion of Regulatory T Cells. Curr Protoc Immunol. 1999;30 suppl:15.13.1–15.13.10.

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