This study describes a novel murine model of chronic intestinal inflammation induced by the hapten reagent 2,4,6-trinitrobenzene sulfonic acid (TNBS). Rectal administration of low doses of TNBS in BALB/c and SJL/J mice resulted in a chronic transmural colitis with severe diarrhea, weight loss, and rectal prolapse, mimicking some characteristics of Crohn's disease in humans. The colons of TNBS-treated mice showed infiltration of CD4+ T cells and high levels of interferon (IFN)-γ mRNA. Isolated lamina propria (LP) CD4+ T cells from TNBS-treated mice exhibited a Th1 pattern of cytokine secretion, with increased IL-2 and IFN-γ levels and decreased IL-4 levels compared to control mice. Administration of monoclonal anti-IL-12 antibodies to TNBS-treated mice at early (5 days) and late (20 days) stages of colitis led to significant improvement in clinical and histopathological aspects of the disease, often completely abrogating established colitis. LP CD4+ T cells from anti-IL-12-treated mice failed to secrete IFN-γ upon in vitro stimulation. These findings demonstrate the pivotal role of IL-12 and IFN-γ in TNBS-induced chronic intestinal inflammation and suggest the potential therapeutic utility of anti-IL-12 antibodies in patients with Crohn's disease.This study describes a novel murine model of chronic intestinal inflammation induced by the hapten reagent 2,4,6-trinitrobenzene sulfonic acid (TNBS). Rectal administration of low doses of TNBS in BALB/c and SJL/J mice resulted in a chronic transmural colitis with severe diarrhea, weight loss, and rectal prolapse, mimicking some characteristics of Crohn's disease in humans. The colons of TNBS-treated mice showed infiltration of CD4+ T cells and high levels of interferon (IFN)-γ mRNA. Isolated lamina propria (LP) CD4+ T cells from TNBS-treated mice exhibited a Th1 pattern of cytokine secretion, with increased IL-2 and IFN-γ levels and decreased IL-4 levels compared to control mice. Administration of monoclonal anti-IL-12 antibodies to TNBS-treated mice at early (5 days) and late (20 days) stages of colitis led to significant improvement in clinical and histopathological aspects of the disease, often completely abrogating established colitis. LP CD4+ T cells from anti-IL-12-treated mice failed to secrete IFN-γ upon in vitro stimulation. These findings demonstrate the pivotal role of IL-12 and IFN-γ in TNBS-induced chronic intestinal inflammation and suggest the potential therapeutic utility of anti-IL-12 antibodies in patients with Crohn's disease.