Editors' ChoiceGastroenterology

Targeting Targets for Treatment in Inflammatory Bowel Disease

See allHide authors and affiliations

Science Translational Medicine  11 May 2011:
Vol. 3, Issue 82, pp. 82ec67
DOI: 10.1126/scitranslmed.3002596

Inflammatory bowel disease (IBD) is a messy business. Flares of diarrhea, bleeding, and discomfort are only some of the symptoms a person can experience. The cornerstone of therapy is to stop the inflammation and thus the destruction of bowel tissue. During a bout of IBD, circulating leukocytes migrate to the inflamed gut, a process that is regulated by cell adhesion molecules as well as by chemokines and chemokine receptors. Drugs that disrupt the migration of these leukocytes can benefit patients, and not-yet-identified molecular targets could point to new drugs with superior properties.

In this study, the authors used microarrays to assess the effect of infliximab—a therapeutic antibody directed against tumor necrosis factor–α (TNF-α) that is used to treat IBD—on intestinal mucosal gene expression in patients. They measured leukocyte and endothelial cell adhesion molecules in patients with Crohn’s ileitis, Crohn’s colitis, and ulcerative colitis and in healthy control subjects; a biopsy was obtained from the small or large intestine before and after infliximab treatment. The authors used quantitative reverse transcriptase polymerase chain reaction, immunohistochemistry, and Western blotting to confirm the microarray data.

Most of the cell adhesion molecule genes that were up-regulated in active IBD patients significantly decreased after infliximab therapy. Patients with IBD of the colon who responded to infliximab showed persistent elevation only of the chemokines CCL20 and CXCL1-2 compared with controls. These elevations, the authors concluded, may predispose a patient to IBD relapse. Patients with IBD of the ileum had increased expression of an array of genes (MADCAM1; THY1; PECAM1; CCL28; CXCL1, -2, -5, -6, and -11; and interleukin-8 IL-8) and decreased CD58 before therapy; these genes were restored to normal (control) levels after infliximab. In addition to the constituents of the already studied MADCAM1 pathway, PECAM1 and the chemokines CCL20 and IL-8 are worthy targets to explore for new IBD drugs. Although the gut-specific chemokine TECK is an apparently attractive target, its expression was found to be limited to the small bowel, and it was not up-regulated in IBD. The authors concluded that on the basis of their findings, improvements in IBD treatment may come from further development of therapies that inhibit the migration of inflammatory leukocytes into the gut.

I. Arijs et al., Mucosal gene expression of cell adhesion molecules, chemokines, and chemokine receptors in patients with inflammatory bowel disease before and after infliximab treatment. Am. J. Gastroenterol. 106, 748–761 (2011). [Abstract]

Stay Connected to Science Translational Medicine

Navigate This Article