HAPTEN-INDUCED MODEL OF MURINE INFLAMMATORY BOWEL-DISEASE - MUCOSAL IMMUNE-RESPONSES AND PROTECTION BY TOLERANCE

We report here a murine model for experimental chronic colitis where a dministration of trinitrobenzene sulfonic acid (TNBS) in 50% ethanol i nduced inflammation of large intestine in susceptible (C3H/HeJ and BAL B/c) but not resistant (C57BL/6 and DBA/2) mouse strains. We queried w hether mucosal trinitrophenyl (TNP)-specific B cell responses were ind uced in mice with TNBS-induced colitis, and if induction of tolerance to TNBS by oral administration of this hapten protected mice from deve lopment of colitis. Isotypes acid subclasses of polyclonal and TNP-spe cific Ab-forming cells (AFC) were assessed in mucosal and peripheral l ymphoid tissues of C3H/HeJ mice with TNBS-induced colitis. Increased n umbers of IgA- and IgG-secreting cells were found in the inflamed colo n lamina propria, inflamed colonic tissue also contained high frequenc ies of IgG anti-TNP AFC (predominantly of IgG1, IgG2a, and IgC2b subcl asses); however, anti-TNP responses in noninflammed mucosal tissues of mice with colitis exhibited dominant IgA and IgM with low IgG anti-TN P responses. CD4(+) T cells stimulated with TNP-splenocytes produced m ore IFN- gamma and less IL-4, suggesting a Th1-type response. Oral adm inistration of TNBS before induction of colitis markedly decreased muc osal anti-TNP responses and completely inhibited anti-TNP IgG2a and Ig G2b responses. Control mice did not show inhibition of anti-TNP AFC re sponses or TNBS-induced colitis. Intracolonic sensitization of suscept ible C3H/HeJ mice with TNBS induces a localized IgG anti-TNP B cell re sponse in the inflamed tissue, whereas prior oral administration of TN BS results in unresponsiveness to this agent and protects mice from de velopment of TNBS-induced colitis.