Colonic administration of a hapten, 2,4,6-trinitrobenzene sulphonic acid (TNBS) has been shown to induce colitis in rats. We are using this model to investigate the role of colonic antigens in the immunopathology. In this study, we show that colitis can be suppressed by oral administration of haptenized colonic antigens prior to the TNBS enema. Moreover, our data suggest that haptenization of the colonic antigens is not essential because oral feeding of non haptenized colonic antigens too protects rats from TNBS-induced colitis. Thus, unmodified colonic antigens may be involved in the induction of oral tolerance, and possibly in the pathogenesis in this model of colitis. Further, we show that the protective immunity or oral tolerance induced by non haptenized colonic antigens can be passively transferred to naïve rats by mesenteric T lymphocytes. Interestingly, oral feeding of small intestinal antigens, haptenized and non haptenized, does not protect rats from colitis, suggesting a specific role for colonic antigens. These data underscore the usefulness of this rat model in the identification of pathogenic antigens in colitis and in the development of therapeutic strategies based on oral tolerance.