Antibodies to interleukin 12 abrogate established experimental colitis in mice.

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.

• Authors: M F Neurath, I Fuss, B L Kelsall, E Stüber, W Strober
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 182 Issue 5 Pg. 1281-90 (Nov 01 1995) ISSN: 0022-1007 [Print] United States
• PMID: 7595199 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Interleukin-12
• Interferon-gamma
• Trinitrobenzenesulfonic Acid

Topics

• Animals
• Antibodies, Monoclonal (immunology, therapeutic use)
• Base Sequence
• CD4 Lymphocyte Count
• Colitis (chemically induced, immunology)
• Colon (immunology, pathology)
• Crohn Disease
• Disease Models, Animal
• Interferon-gamma (physiology)
• Interleukin-12 (antagonists & inhibitors, immunology, physiology)
• Lymphocyte Activation
• Mice
• Mice, Inbred BALB C
• Mice, Inbred Strains
• Molecular Sequence Data
• Spleen (immunology, pathology)
• Trinitrobenzenesulfonic Acid (toxicity)