Experimental Disease Models

The number of experimental IBD models is large and continues to expand (Table 2).2,21,22 Simplistically, they all manifest an intense intestinal inflammation, a consequence of an aberrant, chronic immune response triggered by enteric microflora or disruption of the mucosal barrier. Disruption of the mucosal barrier, either genetically, as evidenced by the phenotype of the Mdr1a ~/ ~ mice, or artificially by exposure of the GI tract to DSS or TNBS generates a fairly reproducible colitic phenotype resembling UC. However, animals treated in pathogen-free environments or coadministered antibiotics have a far lower disease severity and incidence.

The Mdr1a ~/ ~ mouse model is one of the few genetic disease models that develop a colitic phenotype in the absence of immune dysfunction. This is in contrast to virtually all other genetically targeted mice, which develop colitis as a result of either impaired immune function, a cytokine imbalance, or colitis that can be induced by reconstituting naive (CD4 + CD45Rbhi) T cells into severe combined immunodeficiency (SCID) mice. Most of the experimental models of IBD in mice have inflammation only in the colon and resemble UC. The one striking exception to this is the SAMP1/Yit mouse and the derivative SAMP1/YitFc strain. These mice spontaneously develop a Crohn's-like transmural ileitis as early as 10 weeks of age, accompanied by prominent muscular hypertrophy, fibrosis, and activation of mesenteric lymph node lymphocytes, which produce high levels of interferon g (IFN-g). Furthermore, a subgroup of SAMP1/YitFc mice (~5%) also develops perianal fistulating disease.

The common underlying characteristic of the transgenic models of colitis is a chronic uncontrolled, mostly Tcell-mediated inflammatory response. In many incidences, these models have helped inform the potential of new IBD treatment approaches and modalities, whether investigated clinically,1,23 such as anti-TNF-a antagonists (Enbrel, CDP-870, Remicade/infliximab, and Humira/adalimumab), anti-IL12 mAbs,24 rIL10,25 intracellular adhesion molecule (ICAM) antisense oligonucelotides (alicaforsen/ISIS 2302), or in preclinical models.

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