3rd Annual BMRP Investigator Meeting - Abstract

Patients with Active Inflammatory Bowel Disease Lack Immature Peripheral Blood Dendritic Cells that Show an Aberrant Response to Microbial Surrogate Stimuli

Daniel C. Baumgart^a, Diana Metzke, Bertram Wiedenmann and Axel U. Dignass

Department of Medicine and Division of Hepatology and Gastroenterology, Charité Medical Center-Virchow Hospital, Medical School of the Humboldt-University of Berlin (Berlin, Germany)

Background: Breakdown of tolerance against the commensal microflora is believed to be a major factor in the pathogenesis of inflammatory bowel disease (IBD).  Dendritic cells (DC) have been implicated in this process in various animal models, while data on human DC in IBD are very limited.

Patients and Methods: Peripheral blood was obtained from 106 patients (Crohn’s disease (CD) n=49, ulcerative colitis (UC) n=57) and healthy controls (n=19).  Disease activity was scored using the modified Truelove Witts (MTWSI) for UC and the Harvey Bradshaw severity indices (HBSI) for CD.  FACS analysis was used to identify, enumerate and phenotype DC and to assess apoptosis.  DC were also cultured and stimulated with CpG ODN 2006, and LPS, or supernatants from E. coli Nissle (EcN) and E. coli PZ873 (EcPZ873).

Results: IBD patients in remission (PDC UC: 0.39%, CD: 0.35%, MDC-1 UC: 0.23%, CD: 0.22% of PBMC) have slightly lower numbers of circulating DC compared with healthy controls (PDC 0.41%, MDC-1 0.25% of PBMC).  In acute flare-ups, IBD patients experience a significant drop of DC (PDC UC: 0.04%, CD: 0.11%, MDC-1 UC: 0.11%, CD: 0.14% of PBMC) that correlates with disease activity (Correlation Coefficients: PDC MTWSI: 0.93, HBSI: 0.79; MDC-1 MTWSI: 0.75, HBSI: 0.81).  Moreover, both express a4b7-integrin and display an immature phenotype, which rapidly changes upon culture and stimulation.  EcN induced significantly more early apoptosis and cell death in DC than the respective, non-hemolytic control strain EcPZ873.  A clear dose response correlation was established in dose escalation studies.

Conclusion: IBD patients lack immature blood DC during flare-ups that possibly migrate to the gut.  An aberrant response to microbial surrogate stimuli suggests a disturbed interaction with commensals.  Preliminary evidence suggests a modulation of DC function by probiotic bacteria such as EcN.

^aPrincipal Investigator