Infliximab: mechanism of action beyond TNF-alpha neutralization in inflammatory bowel disease.
Infliximab, a chimeric antibody to tumour necrosis factor-alpha (TNF-alpha), holds much promise for the treatment of patients with Crohn's disease. On the cellular level, infliximab affects survival and, as presented by Agnholt et al. in this issue of the journal, inhibits GM-CSF (granulocyte-macrophage colony-stimulating factor) production by intestinal T lymphocytes. Future studies will reveal whether the pro-apoptotic effect of infliximab is linked to its inhibition of endogenous GM-CSF expression in T cells. Treatment of Crohn's disease, a severe chronic intestinal disorder, may at times be challenging as it can be refractory to routine therapy. Among novel therapeutic strategies, agents that neutralize tumour necrosis factor-alpha (TNF-alpha) are of particular interest because of the crucial role of TNF-alpha in sustaining chronic mucosal inflammation. The exact mechanism of the anti-TNF action, apart from direct activity that neutralizes cytokines, is not fully understood. Cellular effects of TNF-alpha neutralizing treatment include an increased susceptibility to apoptosis of intestinal mucosal T cells. A novel pathway of anti-TNF-alpha interaction with T cells has been presented in the current issue of this journal. Agnholt et al. have found that in-vivo or in-vitro administration of infliximab, a chimeric antibody to TNF-alpha, resulted in a decreased production of GM-CSF (granulocyte-macrophage colony-stimulating factor) by T cells. Infliximab related down-regulation of TNF-alpha induced GM-CSF expression may be one of the mechanisms by which this drug increases the rate of apoptosis in T cells.
Kirman
Irena
I
Department of Surgery, Columbia University, New York, NY 10032, USA. ik139@columbia.edu
Whelan
Richard L
RL
Nielsen
Ole H
OH
D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D003424:Crohn Disease / Q000188:drug therapy* / Q000276:immunology; D005765:Gastrointestinal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D006801:Humans; D000069285:Infliximab; D013601:T-Lymphocytes / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D000911:Antibodies, Monoclonal; D005765:Gastrointestinal Agents; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000069285:Infliximab