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TH17 Cell Induction and Effects of IL-17A and IL-17F Blockade in Experimental Colitis

Wedebye Schmidt, Esben Gjerløff MSc, PhD*; Larsen, Hjalte List MSc*; Kristensen, Nanna Ny MSc, PhD*; Poulsen, Steen Seier MD, PhD; Lynge Pedersen, Anne Marie DDS, PhD; Claesson, Mogens Helweg DMSc*; Pedersen, Anders Elm MD, PhD*

doi: 10.1097/MIB.0b013e318286fa1c
Original Basic Science Articles

Background: T helper (TH) 17 cells are believed to play a pivotal role in development of inflammatory bowel disease, and their contribution to intestinal inflammation has been studied in various models of colitis. TH17 cells produce a range of cytokines, some of which are potential targets for immunotherapy. However, blockade of IL-17A alone with secukinumab was not effective in Crohn’s disease. In this regard, the pathogenic impact of IL-17A versus IL-17F during intestinal inflammation is still unresolved.

Methods: Development of IFN-γ–producing, IL-17A–producing, and IL-17F–producing CD4+ T cells was analyzed in the CD4+CD25 T-cell transfer model of colitis at varying degrees of colitis. The pathogenic roles of IL-17A and IL-17F were investigated by treating colitic mice with neutralizing antibodies against these 2 cytokines.

Results: We found that colitis development was associated with an increase in IL-17A–producing TH17 cells in spleen, mesenteric lymph nodes, and lamina propria. In contrast, the relative abundance of IFN-γ–producing TH1 cell was stable in all 3 organs during progression of colitis, and the frequency of IFN-γ+IL-17A+ double-positive cells declined in spleen and mesenteric lymph node but not in lamina propria. IL-17F was coexpressed in TH17 cells and IFN-γ+IL-17A+ double positive but not in TH1 cells and its expression inversely correlated with colitis development. In vivo neutralization of both IL-17A and IL-17F ameliorated colitis in particular at early administration, whereas neutralization of IL-17A or IL-17F alone was inefficient.

Conclusions: TH17 cell development correlates with colitis progression, and concurrent neutralization of their cytokine products IL-17A and IL-17F ameliorates intestinal inflammation. These findings suggest combined IL-17A and IL-17F blockade as a potential strategy in inflammatory bowel disease therapy.

Article first published online 17 May 2013

*Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark;

Department of Biomedical Science, University of Copenhagen, Copenhagen, Denmark; and

Department of Odontology, Section of Oral Medicine, Clinical Oral Physiology, Oral Pathology & Anatomy, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.

Reprints: Anders Elm Pederson, MD, PhD, Department of International Health, Immunology and Microbiology, Panum Institute, University of Copenhagen, Building 18.3.26, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark (e-mail: elmpedersen@sund.ku.dk).

Supported by the Danish Agency for Science, Technology and Innovation, the Colitis Crohn’s Foundation, the Aage and Johanne Louis-Hansen Foundation, the Aase and Ejnar Danielsen Foundation, the Augustinus Foundation, and the Lundbeck Foundation.

The authors have no conflicts of interest to disclose.

Received November 02, 2012

Accepted January 9, 2013

© Crohn's & Colitis Foundation of America, Inc.
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