Final Progress Report
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
Lay Summary
Our first aim was to study the importance of the molecule CD44v7 in patients with Crohn´s disease (CD). We could show that high numbers of immune cells in the gut from patients with CD carry CD44v7 but not cells from ulcerative colitis (UC). An antibody against CD44v7 was able to induce cell death in CD. Memory cells play an important role in this disease and especially those cells were highly susceptible to anti-CD44v7 treatment and died. Usually, programmed cell death is mediated by two different pathways. We found out that the CD44v7 antibody treatment induces the so called mitochondrial pathway, but not the pathway via the death receptor Fas. The pathway mentioned first is defect in CD. We suggest that treatment of CD patients with anti-CD44v7 might be a new therapeutic strategy to enhance the symptoms of this disease.
As a next step we examined a molecule that binds to CD44v7. It is called osteopontin (OPN). We found increased concentrations of this molecule in the blood of patients with CD, but not with UC. Furthermore OPN concentration correlated with disease activity in CD. The main producers of OPN in the blood were phagocytes and special antigen presenting cells, so called plasma dendritic cells. According to the data revealed from blood, increased amounts of OPN were detected in the gut when the disease activity was high. Again, phagocytes and epithelial cells were the main producer of this molecule. These results indicate an association of OPN production and inflammatory bowel diseases like CD, but not UC. So it was very surprising that mice deficient for OPN were not protected from experimental acute colitis and developed signs of inflammation in the gut that are very similar to CD. It even seems that symptoms were stronger in these mice than in normal mice. It is known that OPN is also important for tissue repair. So we suggest that OPN supports tissue healing and OPN release reflects tissue repair in patients with active CD.
At least we wanted to test if a molecule consisting of CD44 variants might be able to catch binding partners of CD44 variants and though suppressing inflammation in the intestine. Indeed, our molecule was able to diminish symptoms of experimental colitis in mice and induced production of anti-inflammatory soluble molecules as IL-10 in the gut. Nevertheless in vitro it neither reduced cell division nor cell death. So we conclude that our CD44 variant molecule catches binding partners of CD44 variants in vivo and so reduces inflammation while in vitro this molecule had no effect, because binding partners are absent.
To summarize: CD44v7 is a molecule that seems to play an important role in CD and targeting itself or binding partners could enhance symptoms of CD, however targeting of OPN had converse effects in mice, because OPN does not only fulfill pro-inflammatory function, but it is also involved in tissue healing.