LESSONS IN IBD PATHOGENESIS FROM NEW ANIMAL-MODELS OF SPONTANEOUS COLITIS

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 in to the pathogenesis of human inflammatory bowel disease (IBD)I Spontan eous colitis resulting from deletion of genes encoding key immunoregul atory cytokines (interleukin [IL]-2, IL-IO and transforming growth fac tor [TGF]-beta) and T cell receptors (TCRs) demonstrates that an intac t mucosal immune response prevents colitis. The TCR KO model incrimina tes B lymphocytes in spontaneous colonic inflammation - TCR KO with in tact B cells causes colitis, but simultaneous deletion of T and B cell s does not. This model and induction of colitis in severe combined imm unodeficient (SCID) mice by constitution with one T cell subset (CD45R H(hi)), but prevention by addition of the CD45RB(lo) subset, 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 absenc e of chronic intestinal inflammation in germ-free (sterile)IL-2 KO mic e and human leukocyte antigen (HLA)-B27 transgenic rats, and attenuate d inflammation in IL-2 and rr.-lo KO mice raised under specific pathog en-free conditions. The fundamental role of host genetic susceptibilit y in chronic intestinal inflammation and systemic manifestations is es tablished by development of spontaneous colitis and perianal inflammat ion in C3H/HeJ Bir substrain mice and HLA-B27 transgenic rats.