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.
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.
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.
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.
Supplemental Digital Content is Available in the Text.Article first published online 30 May 2012
*Department of Gastroenterology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
†Laboratory of Clinical Immunology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium
‡Department of Morphology and Molecular Pathology, University Hospitals, Leuven, Belgium
§Xencor, Inc., Monrovia, California, USA.
Reprints: Clémentine Perrier, Department of Gastroenterology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, O&N 1, Herestraat 49, box 811, 3000 Leuven, Belgium (e-mail: clementine.perrier@med. kuleuven.be).
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.ibdjournal.org).
Partly supported by a grant from the Swiss Science Research Foundation (PBLAP3-129427/1) (to C.P.).
Received April 12, 2012
Accepted April 30, 2012