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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.
Highlights
Attenuation of spontaneous intestinal inflammation in IL-2 and IL10 deficient mice raised in a pathogenfree environment and lack of evidence of colitis in IL-2 KO mice and HLAB27/b2m mice living in germ-free conditions dramatically illustrate the critical pathogenetic role of ubiquitous luminal bacterial constituents
SUMMARY AND CONCLUSIONS Chronic intestinal inflammation that develops in response to spontaneous gene mutations, targeted deletion or overexpression of specific genes or selective manipulation of lymphocytes subsets can provide important insights into the mechanisms of intestinal inflammation [22]
Models of Transforming growth factor (TGF)-b1 KO, ab T cell receptors (TCRs) deletion and CD45RBhi reconstitution of severe combined immunodeficient (SCID) mice clearly demonstrate the consequences of ineffective T lymphocyte suppression and suggest that T cell suppression is critical to normal mucosal homeostasis
Summary
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. Overexpression (transgenic) and deletion (knockout [KO]) of specific human leukocyte antigen (HLA), cytokine and T cell receptor (TCR) genes in rodents have provided important and sometimes surprising models of spontaneous colitis (Table 2). These new models, in combination with a spontaneous mutation in C3H/HeJ mice, restoration of T cell subsets to immunocompromised mice and induction of intestinal inflammation by PG-PS, indomethacin or trinitrobenzene-sulphonic acid in inbred rodent strains, have provided novel insights into mechanisms of chronic intestinal and systemic inflammation. Strain Wild type TCR d KO Nude RAG-1 KO TCR a KO TCR b KO TCR b KO x d KO Class II MHC KO
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