INHIBITION OF TH1 RESPONSES PREVENTS INFLAMMATORY BOWEL-DISEASE IN SCID MICE RECONSTITUTED WITH CD45RB(HI) CD4(+) T-CELLS

We have described a murine model of IBD that was induced in C.B-17 scid mice by transfer of the CD45RB(hi) subpopulation of CD4(+) T cells from normal BALB/c mice and could be prevented by cotransfer of the CD45RB(lo) CD4(+) T cell subset. Here we have dissected the mechanism of pathogenesis of IBD in this model and used this information for rational immunotherapy of the disease. CD4(+) cells from diseased mice displayed a highly polarized Th1 pattern of cytokine synthesis upon polyclonal stimulation in vitro. The administration of anti-IFN gamma MAb to mice soon after T cell transfer prevented development of colitis for up to 12 weeks. Continual neutralization of TNF with anti-TNF MAbs reduced the incidence of severe disease; however, neutralization of TNF during only the first 3-4 weeks had no effect. Severe colitis was completely abrogated in mice treated systemically with rlL-10, but not with rlL-4.