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

Background: T helper (T-H) 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. T(H)17 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--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 T(H)17 cells in spleen, mesenteric lymph nodes, and lamina propria. In contrast, the relative abundance of IFN--producing T(H)1 cell was stable in all 3 organs during progression of colitis, and the frequency of IFN-+IL-17A(+) double-positive cells declined in spleen and mesenteric lymph node but not in lamina propria. IL-17F was coexpressed in T(H)17 cells and IFN-+IL-17A(+) double positive but not in T(H)1 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:T(H)17 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.