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 chronic transmural colitis with severe diarrhea, weight loss, and rectal prolapse, resembling some features of Crohn's disease. The colon of TNBS-treated mice on day 7 showed infiltration of CD4⁺ T cells and high levels of IFN-γ mRNA. Isolated LP CD4⁺ T cells from TNBS-treated mice stimulated with anti-CD3 and anti-CD28 antibodies exhibited a Th1 pattern of cytokine secretion, with increased IL-2 and IFN-γ and decreased IL-4 compared to control mice. Administration of monoclonal anti-IL-12 antibodies to TNBS-treated mice at 5 or 20 days after induction led to significant improvement in clinical and histopathological aspects of the disease, often abrogating established colitis. LP CD4⁺ T cells from anti-IL-12-treated mice failed to secrete IFN-γ upon in vitro stimulation. The data demonstrate the pivotal role of IL-12 and IFN-γ in TNBS-induced chronic intestinal inflammation and suggest the potential utility of anti-IL-12 antibodies in patients with Crohn's disease. The study also highlights the similarity between TNBS-induced colitis and human Crohn's disease, supporting the use of anti-IL-12 antibodies as a potential therapeutic approach.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 chronic transmural colitis with severe diarrhea, weight loss, and rectal prolapse, resembling some features of Crohn's disease. The colon of TNBS-treated mice on day 7 showed infiltration of CD4⁺ T cells and high levels of IFN-γ mRNA. Isolated LP CD4⁺ T cells from TNBS-treated mice stimulated with anti-CD3 and anti-CD28 antibodies exhibited a Th1 pattern of cytokine secretion, with increased IL-2 and IFN-γ and decreased IL-4 compared to control mice. Administration of monoclonal anti-IL-12 antibodies to TNBS-treated mice at 5 or 20 days after induction led to significant improvement in clinical and histopathological aspects of the disease, often abrogating established colitis. LP CD4⁺ T cells from anti-IL-12-treated mice failed to secrete IFN-γ upon in vitro stimulation. The data demonstrate the pivotal role of IL-12 and IFN-γ in TNBS-induced chronic intestinal inflammation and suggest the potential utility of anti-IL-12 antibodies in patients with Crohn's disease. The study also highlights the similarity between TNBS-induced colitis and human Crohn's disease, supporting the use of anti-IL-12 antibodies as a potential therapeutic approach.