Neutralization of membrane TNF, but not soluble TNF, is crucial for the treatment of experimental colitis.
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 CD45RB(hi) 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.
Department of Gastroenterology, Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium.
Clémentine
C
Perrier
Gert
G
de Hertogh
Jonathan
J
Cremer
Severine
S
Vermeire
Paul
P
Rutgeerts
Gert
G
Van Assche
David E
DE
Szymkowski
Jan L
JL
Ceuppens
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004334:Drug Administration Schedule; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D013601:T-Lymphocytes / Q000378:metabolism; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000627:therapeutic use
D000893:Anti-Inflammatory Agents; D058846:Antibodies, Monoclonal, Murine-Derived; D015415:Biomarkers; D016207:Cytokines; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; C540591:XENP 1595