BACKGROUND: Mucosal addressin cell-adhesion molecule (MAdCAM)-1, which is overexpressed on gut endothelium in active Crohn's disease (CD), promotes intestinal recruitment of integrin α(4)β(7)(*) T cells that sustain chronic inflammation. As tumor necrosis factor alpha (TNF)-α, a cytokine centrally involved in CD, modulates gut endothelial adhesion molecules, we here explored the in vivo and ex vivo effects of TNF-α blockade on MAdCAM-1 expression in CD.
METHODS: MAdCAM-1 was determined by immunoblotting in colonic biopsies collected before and 10 weeks after either infliximab or adalimumab treatment in CD patients, and in CD biopsies incubated with either infliximab or adalimumab or control IgG(1). Integrin β(7)(*) circulating T cells were analyzed by flow cytometry.
RESULTS: MAdCAM-1 significantly decreased after either infliximab or adalimumab treatment in responder but not in nonresponder patients. In parallel, an increase of circulating β(7)(*) T cells was found in responder patients only. A marked downregulation of MAdCAM-1 was observed in CD biopsies cultured with either infliximab or adalimumab in comparison to IgG(1)-treated biopsies.
CONCLUSIONS: Our findings showing that MAdCAM-1 is downregulated by TNF-α blockade point to a novel mechanism of action of anti-TNF-α antibodies in CD.
- Anti-Inflammatory Agents, Non-Steroidal/pharmacology
- Antibodies, Monoclonal/pharmacology
- Antibodies, Monoclonal, Humanized/pharmacology
- Blotting, Western
- Colon/drug effects
- Crohn Disease/drug therapy
- Down-Regulation/drug effects
- Drug Administration Schedule
- Flow Cytometry
- Integrin beta Chains/metabolism
- Middle Aged
- Treatment Outcome