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P067. Dysregulation of human dendritic cell function in ulcerative colitis

E. Mann1, D. Bernardo1, S. Vallejo-Diez2, S. Peake3, H.O. Al-Hassi1, B. Martinez-Abad4, E. Montalvillo2, C. Tee1, J. Landy3, N. Daulatzai3, A. Hart5, H. Nunez6, L. Fernandez Salazar7, J.A. Garrote8, E. Arranz2, S. Knight1

1Antigen Presentation Research Group, Imperial College, London, United Kingdom; 2University of Valladolid, Dept of Paediatrics & Immunology/Immunology Lab, Valladolid, Spain; 3St Mark's Hospital, London, United Kingdom; 4Universidad de Valladolid, Spain; 5St Mark's Hospital, Gastroenterology, London, United Kingdom; 6Hospital Rio Carrion, Spain; 7Hospital Clinico Universitario De Valladoilid, Valladolid, Spain; 8University of Valladolid, Dept of Paediatrics & Immunology/Ibgm-Csic. Research Unit, Valladolid, Spain

Background: Dendritic cells (DC), “commanders-in-chief” of the immune system, determine development of either immunogenic or tolerogenic immune responses, and imprint homing properties on T‑cells. In the gut, disruption of the balance between immunity and tolerance contributes to inflammatory bowel disease (IBD) pathogenesis. Indeed, alterations in gut DC have been found in IBD. We investigated the role of human DC in IBD.

Methods: Flow cytometry was used to characterize the phenotype and function of human blood DC from active ulcerative colitis (UC) patients (no treatment, 5ASA or AZA only) and from healthy controls. The cytokine content of colonic biopsy supernatants (Bx-SN) from inflamed and non-inflamed intestinal areas of active UC patients (inflamed/non-inflamed Bx-SN) was determined by ELISA. We also determined whether conditioning healthy blood DC with Bx-SN altered DC phenotype and function (by flow cytometric methods).

Results: DC were used to stimulate allogeneic T‑cells. Both DC from UC patients (UC-DC) and DC conditioned with inflamed Bx-SN induced a skin-homing profile on stimulated T‑cells via expression of skin-homing markers CLA and CCR4. UC-DC increased production of IL‑17, but reduced production of IL‑10 by stimulated T‑cells, compared to healthy DC. IL‑6 was the predominant cytokine found in inflamed Bx-SN, and its concentration correlated with Mayo endoscopic score. IL‑13 was below the detection limit. Inflamed Bx-SN conditioning reduced production of IL‑10 by DC but increased IL‑6 and IL‑12 production, compared to DC conditioned with non-inflamed Bx-SN.

Conclusions: The ability of UC-DC and inflamed Bx-SN-conditioned DC to induce a skin-homing profile on T‑cells has implications in vivo of directing of effector cells to the skin. This provides an explanation for extra-intestinal manifestations of IBD affecting cutaneous sites (including pyoderma gangrenosum or erythema nodosum). Our results highlight the role of IL‑6 in UC, and question the concept of UC as a Th2 disease. The increased IL‑17 production by T‑cells stimulated with UC-DC, taken with increased IL‑6/IL‑12 production by inflamed Bx-SN-conditioned DC, highlights the importance of the Th1/Th17 axis in UC. Our results provide new targets for IBD immunotherapy and demonstrate that DC function can be modified by the surrounding microenvironment.