Lay Summary

Proposal No. IBD-0079
Principal Investigator:  Bianca Maria Wittig, M.D.
Applicant Organization:  University Hospital Benjamin Franklin, Free University Berlin (Germany)
Project Title:  Modulation of CD44: a new therapeutic approach in inflammatory bowel disease?
Period of Award:  December 1, 2003 - May 31, 2006

In inflammatory bowel disease, a defective control of the immune system plays a central role.  CD44 is a cell surface molecule that is detected on a variety of immune cells and mediates cell-cell contact or cell to the tissue layer contact.  In cell activation and inflammation, specific molecules of the CD44 protein family, CD44v6 and v7, are strongly upregulated.  Osteopontin, physiologically secreted by bone cells, macrophages and T cells, is a newly identified ligand of CD44v7.  It has been shown that interaction of the ligand osteopontin and CD44 mediates moderate inflammation, but also tissue damage in severe, chronic inflammation.

In a mouse colitis model, it was demonstrated that targeted deletion or blockade of the molecule CD44v7 protects and even cures mice from severe intestinal inflammation and wasting disease.  The protective effect was associated with an increased rate of immune cell death, thus eliminating inflammatory infiltrates in the gut mucosa.  Therefore, expression of CD44v7 seems to be essential for an ongoing immune response in the gut.  Comparable to the animal studies, CD44v7 is also upregulated in lamina propria lymphocytes of Crohn’s disease patients, but not in ulcerative colitis or acute diverticulitis or appendicitis.  Preliminary data indicate that blockade of CD44 with an antibody induces the production of regulatory molecules in intestinal cells that suppress the ongoing inflammatory immune response.

In this grant proposal, we want to correlate CD44 expression and function with disease progression in patients with Crohn’s disease.  The anti-inflammatory effect and mechanisms of blocking substances, such as antibodies, soluble receptor-molecules and blocking osteopontin peptides, will be tested in isolated intestinal cells from Crohn’s disease patients.  The therapeutic usefulness of these new substances will be evaluated in a mouse model of experimental colitis.  The long-term goal is to find out if modulation of the CD44-osteopontin interaction may be a target for a new therapeutic approach in patients with Crohn’s disease.