Neutralization of membrane TNF, but not soluble TNF, is crucial for the treatment of experimental colitis

Authors

  • Clémentine Perrier PhD,

    Corresponding author
    1. Department of Gastroenterology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
    2. Laboratory of Clinical Immunology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium
    • Department of Gastroenterology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, O&N 1, Herestraat 49, box 811, 3000 Leuven, Belgium
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  • Gert de Hertogh MD, PhD,

    1. Department of Morphology and Molecular Pathology, University Hospitals, Leuven, Belgium
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  • Jonathan Cremer,

    1. Department of Gastroenterology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
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  • Severine Vermeire MD, PhD,

    1. Department of Gastroenterology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
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  • Paul Rutgeerts MD, PhD,

    1. Department of Gastroenterology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
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  • Gert Van Assche MD, PhD,

    1. Department of Gastroenterology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
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  • David E. Szymkowski PhD,

    1. Xencor, Inc., Monrovia, California, USA
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  • Jan L. Ceuppens MD, PhD

    1. Laboratory of Clinical Immunology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium
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Abstract

Background:

Agents neutralizing membrane tumor necrosis factor (mTNF) and soluble TNF (sTNF) are widely used for the treatment of inflammatory bowel disease (IBD). Neutralization of mTNF, however, is associated with increased susceptibility to infectious diseases. The aim of this study was to determine whether neutralization of sTNF exclusively, by the use of a dominant negative mutant of TNF (XENP1595), could reduce the severity of colitis in mice.

Methods:

Colitis was induced in immunodeficient mice by transfer of CD45RBhi CD25 T-cells. Once the disease had developed, mice were treated twice a week with XENP1595, phosphate-buffered saline (PBS), anti-TNF monoclonal antibody (mAb), or isotype control. The anti-TNF mAb blocks both mTNF and sTNF. Weights, disease activity index, macroscopic inflammation of the colon, and histological sections were evaluated. T-cell populations from the colon were analyzed by flow cytometry.

Results:

Treatment of mice with XENP1595 did not change the course of the disease, whereas mice treated with anti-TNF mAb recovered weight soon after the first treatment dose. Inflammation in the colon was reduced in mice treated with anti-TNF mAb compared to isotype control-treated animals. Mice treated with XENP1595 had a similar degree of inflammation in the colon as PBS-treated animals. The number of effector and regulatory T-cells in the colon remained unaffected by all treatments.

Conclusions:

Neutralization of sTNF exclusively was unable to induce remission in T-cell-mediated colitis, suggesting that neutralization of mTNF is crucial for the treatment of IBD. (Inflamm Bowel Dis 2012;)

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