We have described a murine model of IBD that was induced in CB-17 scid mice by transfer of the CD45RBhi subpopulation of CD4+ T cells from normal BALB/c mice and could be prevented by cotransfer of the CD45RB’” CD4+ Tcellsubset. Here we havedissected themechanism 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 Thl pattern of cytokine synthesis upon poly clonal stimulation in vitro. The administration of anti-IFNy 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.