Antibodies to interleukin 12 abrogate established experimental colitis in mice.

TLDR

Rectal application of low doses of TNBS in BALB/c and SJL/J mice produces chronic transmural colitis with severe diarrhea, weight loss, and rectal prolapse, mimicking features of human Crohn’s disease. The study aimed to develop a novel murine model of chronic intestinal inflammation using TNBS. The model was induced by rectal application of low doses of TNBS in BALB/c and SJL/J mice, generating chronic transmural colitis. Anti‑IL‑12 monoclonal antibodies administered early or late after TNBS induction markedly improved clinical and histopathological outcomes, abrogated established colitis, and suppressed IFN‑γ production by lamina propria CD4⁺ T cells, underscoring IL‑12 and IFN‑γ as pivotal drivers of this chronic intestinal inflammation and suggesting therapeutic potential for Crohn’s disease.

Abstract

In this study, we describe a novel murine model of chronic intestinal inflammation induced by the hapten reagent 2,4,6-trinitrobenzene sulfonic acid (TNBS). Rectal application 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, an illness that mimics some characteristics of Crohn's disease in humans. The colon of TNBS-treated mice on day 7 was marked by infiltration of CD4+ T cells; furthermore, in situ polymerase chain reaction studies revealed high levels of interferon (IFN)-gamma mRNA in diseased colons. Isolated lamina propria (LP) CD4+ T cells from TNBS-treated mice stimulated with anti-CD3 and anti-CD28 antibodies exhibited a Th1 pattern of cytokine secretion: a 20-50-fold increase in IL-2 and IFN-gamma levels and a 5-fold decrease in IL-4 levels as compared with those of stimulated LP CD4+ T cells from control BALB/c mice. Administration of monoclonal anti-IL-12 antibodies to the TNBS-treated mice both early (at 5 d) and late (at 20 d) after induction of colitis led to a striking improvement in both the clinical and histopathological aspects of the disease and frequently abrogated the established colitis completely. Furthermore, LP CD4+ T cells isolated from anti-IL-12-treated mice failed to secrete IFN-gamma upon in vitro stimulation. In summary, the data demonstrate the pivotal role of IL-12 and IFN-gamma in a TNBS-induced murine model of chronic intestinal inflammation. Furthermore, they suggest the potential utility of anti-IL-12 antibodies in patients with Crohn's disease.