title: TH17 cell induction and effects of IL-17A and IL-17F blockade in experimental colitis.
abstract: 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 CD4CD25 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-γIL-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-γIL-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.
authors.affiliation: Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Esben Gjerløff
authors.initials: EG
authors.lastname: Wedebye Schmidt
authors.forename: Hjalte List
authors.initials: HL
authors.lastname: Larsen
authors.forename: Nanna Ny
authors.initials: NN
authors.lastname: Kristensen
authors.forename: Steen Seier
authors.initials: SS
authors.lastname: Poulsen
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Lynge Pedersen
authors.forename: Mogens Helweg
authors.initials: MH
authors.lastname: Claesson
authors.forename: Anders Elm
authors.initials: AE
authors.lastname: Pedersen
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D003092:Colitis / Q000150:complications / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D005434:Flow Cytometry; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control*; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000276:immunology; D007422:Intestines / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*
chemical_list: D057134:Antibodies, Neutralizing; D020381:Interleukin-17; D007371:Interferon-gamma