Lessons in IBD Pathogenesis from New Animal Models of Spontaneous Colitis

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Abstract
The recent explosion of transgenic and targeted gene deleted (knockout [KO]) rodents has yielded a number of new animal models of spontaneous, chronic intestinal inflammation that have provided novel insights into the pathogenesis of human inflammatory bowel disease (IBD). Spontaneous colitis resulting from deletion of genes encoding key immunoregulatory cytokines (interleukin [IL]-2, IL-10 and transforming growth factor [TGF]-beta) and T cell receptors (TCRs) demonstrates that an intact mucosal immune response prevents colitis. The TCR KO model incriminates B lymphocytes in spontaneous colonic inflammation – TCR KO with intact B cells causes colitis, but simultaneous deletion of T and B cells does not. This model and induction of colitis in severe combined immunodeficient (SCID) mice by constitution with one T cell subset (CD45RHhi), but prevention by addition of the CD45RBlosubset, strongly suggest that T cell subsets down-regulate inflammation in the normal, immunocompetent host. An essential role for normal luminal bacteria in induction and perpetuation of enterocolitis is provided by the absence of chronic intestinal inflammation in germ-free (sterile) IL-2 KO mice and human leukocyte antigen (HLA)-B27 transgenic rats, and attenuated inflammation in IL-2 and IL-10 KO mice raised under specific pathogen-free conditions. The fundamental role of host genetic susceptibility in chronic intestinal inflammation and systemic manifestations is established by development of spontaneous colitis and perianal inflammation in C3H/HeJ Bir substrain mice and HLA-B27 transgenic rats.
Funding Information
  • U.S. Public Health Service (DK 40249, DK 47700, DK 34987)

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