Scientific Abstract

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 dysregulated immune response to bacterial or food antigens plays a major role.  CD44, a cell surface glycoprotein that serves as an adhesion molecule in cell-substrate or cell-cell interactions, is upregulated in acute and chronic inflammation.  Its ligands include osteopontin and the extracellular matrix molecules hyaluronic acid and chondroitin sulfate, all of which can mediate cell-cell interactions that lead to macrophage activation.  In contrast to CD44-standard, which is expressed on a large variety of cells, alternative splicing is strictly regulated and generates variant isoforms of CD44.  These CD44 isoforms serve diverse functions in T cell activation.  The interaction of CD44v7 with the glycoprotein osteopontin has been implicated in either maintaining or reconfiguring the integrity of inflamed tissue.

In a mouse model of experimental colitis, blockade or targeted deletion of CD44v7 protects mice from severe intestinal inflammation by inducing apoptosis in lamina propria mononuclear cells in the inflamed mucosa.  These data are compatible with a blockade of osteopontin function, inducing suppression of apoptosis in inflammatory conditions.  In recent studies, we have investigated CD44 variant isoform expression in patients with inflammatory bowel disease.  In a clinical study, it was shown that CD44v7 is upregulated in lamina propria lymphocytes of Crohn’s disease patients, but not in ulcerative colitis or acute diverticulitis.  Preliminary data indicate that blockade of CD44 with a monoclonal antibody induces the production of the protective cytokine IL-10 in lamina propria mononuclear cells.

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 of a CD44v7 antibody, a CD44 fusion protein or inhibitors such as peptides of the CD44v7 ligand osteopontin will be tested in lamina propria mononuclear cells from Crohn’s disease patients in vitro.  The immunological response in mucosal T cells and antigen presenting cells upon modulation of CD44 will be evaluated by determination of activation markers, T cell subpopulations (e.g., T regulatory cells), cytokine production (IFN-γ, IL-10, IL-4), and cell proliferation or apoptosis.  Finally, we want to examine the CD44 mediated signalling of osteopontin in lamina propria mononuclear cells from Crohn’s disease patients as compared to normal lamina propria cells.  The therapeutic potential of small molecule inhibitors, such as osteopontin peptides or a CD44 fusion protein that target either the receptor or the ligand binding sites, will be tested 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.