3rd Annual BMRP Investigator Meeting - Abstract
Anti-CD44v7 Antibody Specifically Induces the Mitochondrial Apoptosis Pathway that is Defective in Crohn’s Disease
Ute Kretschmer1, Claudia Hayford1, Andreas Stallmach2, Ursula Günthert3, Martin Zeitz1 and Bianca M. Wittig1,a
1Medical Clinic 1, Charité Universitatsmedizin Berlin, Campus Benjamin Franklin (Berlin, Germany); 2Medical Clinic 2, University of the Saarland (Homburg/Saar, Germany); 3Institute of Medical Microbiology, University of Basel (Basel, Switzerland)
In Crohn’s disease, intestinal inflammation is accompanied by excessive survival of immune cells. It appears that promoting immune cell apoptosis has a major impact for the well-established therapeutic approaches. In experimental colitis, we have shown that CD44v7 is essential for development of intestinal inflammation and CD44v7 deletion restores intestinal integrity by apoptosis induction in the lamina propria mononuclear cells (LPMC).
In the present work, we studied the effect of CD44v7-inhibition on LPMC. An upregulation of CD44v7 in inflamed mucosa of Crohn’s disease patients, but not in noninflamed mucosa of these patients or in ulcerative colitis, was observed. In Crohn’s disease, we demonstrated for the first time that blockade of an adhesion molecule, CD44v7, with a monoclonal antibody induces apoptosis in LPMC. This effect was restricted to LPMC from inflamed mucosa, since the apoptosis rate was increased by 61% in inflamed mucosa versus 18% and 4% in cells of noninflamed mucosa or controls (p<0.01). Furthermore, treatment with anti-CD44v7 overcame resistance to CD2-activation-induced cell death in LPMC from diseased mucosa. Anti-CD44v7 antibody-induced apoptosis was independent of the Fas pathway, but associated with a marked upregulation of the pro-apoptotic mitochondrial proteins Bax and 7A6 and subsequent activation of caspase 3. Apoptosis induction was detected on both cell types, activated macrophages and T cells, which might ensure the effective and rapid action in restoring the intestinal mucosa seen in vivo in experimental colitis. However, in CD3/CD28 stimulated T cells, anti-CD44v7 antibody treatment did not affect activation and proliferation via PI3kinase signaling, indicating that CD44v7 does not regulate cellular expansion.
Anti-CD44v7 antibody might be a selective immune modulatory drug for the treatment of Crohn’s disease.
aPrincipal Investigator