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.
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1 November 1995
Article|
November 01 1995
Antibodies to interleukin 12 abrogate established experimental colitis in mice.
M F Neurath,
M F Neurath
Mucosal Immunity Section, National Institutes of Health/National Institute of Allergy and Infectious Diseases/LCI, Bethesda, Maryland 20892-1890, USA.
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I Fuss,
I Fuss
Mucosal Immunity Section, National Institutes of Health/National Institute of Allergy and Infectious Diseases/LCI, Bethesda, Maryland 20892-1890, USA.
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B L Kelsall,
B L Kelsall
Mucosal Immunity Section, National Institutes of Health/National Institute of Allergy and Infectious Diseases/LCI, Bethesda, Maryland 20892-1890, USA.
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E Stüber,
E Stüber
Mucosal Immunity Section, National Institutes of Health/National Institute of Allergy and Infectious Diseases/LCI, Bethesda, Maryland 20892-1890, USA.
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W Strober
W Strober
Mucosal Immunity Section, National Institutes of Health/National Institute of Allergy and Infectious Diseases/LCI, Bethesda, Maryland 20892-1890, USA.
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M F Neurath
Mucosal Immunity Section, National Institutes of Health/National Institute of Allergy and Infectious Diseases/LCI, Bethesda, Maryland 20892-1890, USA.
I Fuss
Mucosal Immunity Section, National Institutes of Health/National Institute of Allergy and Infectious Diseases/LCI, Bethesda, Maryland 20892-1890, USA.
B L Kelsall
Mucosal Immunity Section, National Institutes of Health/National Institute of Allergy and Infectious Diseases/LCI, Bethesda, Maryland 20892-1890, USA.
E Stüber
Mucosal Immunity Section, National Institutes of Health/National Institute of Allergy and Infectious Diseases/LCI, Bethesda, Maryland 20892-1890, USA.
W Strober
Mucosal Immunity Section, National Institutes of Health/National Institute of Allergy and Infectious Diseases/LCI, Bethesda, Maryland 20892-1890, USA.
Online ISSN: 1540-9538
Print ISSN: 0022-1007
J Exp Med (1995) 182 (5): 1281–1290.
Citation
M F Neurath, I Fuss, B L Kelsall, E Stüber, W Strober; Antibodies to interleukin 12 abrogate established experimental colitis in mice.. J Exp Med 1 November 1995; 182 (5): 1281–1290. doi: https://doi.org/10.1084/jem.182.5.1281
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