Inflammatory Bowel Diseases

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

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*

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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.

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

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