TY - JOUR
T1 - TH17 Cell Induction and Effects of IL-17A and IL-17F Blockade in Experimental Colitis
AU - Schmidt, Esben Gjerløff Wedebye
AU - Larsen, Hjalte List
AU - Kristensen, Nanna Ny
AU - Poulsen, Steen Seier
AU - Pedersen, Anne Marie Lynge
AU - Claesson, Mogens Helweg
AU - Pedersen, Anders Elm
PY - 2013/7
Y1 - 2013/7
N2 - 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 +CD252- 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.
AB - 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 +CD252- 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.
U2 - 10.1097/mib.0b013e318286fa1c
DO - 10.1097/mib.0b013e318286fa1c
M3 - Journal article
C2 - 23689808
SN - 1078-0998
VL - 19
SP - 1567
EP - 1576
JO - Inflammatory Bowel Diseases
JF - Inflammatory Bowel Diseases
IS - 8
ER -