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

Esben Gjerløff Wedebye Schmidt; Hjalte List Larsen; Nanna Ny Kristensen; Steen Seier Poulsen; Anne Marie Lynge Pedersen; Mogens Helweg Claesson; Anders Elm Pedersen

doi:10.1097/mib.0b013e318286fa1c

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

Esben Gjerløff Wedebye Schmidt, Hjalte List Larsen, Nanna Ny Kristensen, Steen Seier Poulsen, Anne Marie Lynge Pedersen, Mogens Helweg Claesson, Anders Elm Pedersen

52 Citations (Scopus)

Abstract

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_H17 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 T_H17 cells in spleen, mesenteric lymph nodes, and lamina propria. In contrast, the relative abundance of IFN-γ-producing T_H1 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 T_H17 cells and IFN-γ⁺IL- 17A⁺ double positive but not in T_H1 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_H17 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.

Original language	English
Journal	Inflammatory Bowel Diseases
Volume	19
Issue number	8
Pages (from-to)	1567-1576
Number of pages	10
ISSN	1078-0998
DOIs	https://doi.org/10.1097/mib.0b013e318286fa1c
Publication status	Published - Jul 2013

Access to Document

10.1097/mib.0b013e318286fa1c

https://academic.oup.com/ibdjournal/article-pdf/19/8/1567/23423703/ibd1567.pdf

Cite this

@article{055d6cd65ead4e8096b1d7c5927b96d2,

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 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.",

author = "Schmidt, {Esben Gjerl{\o}ff Wedebye} and Larsen, {Hjalte List} and Kristensen, {Nanna Ny} and Poulsen, {Steen Seier} and Pedersen, {Anne Marie Lynge} and Claesson, {Mogens Helweg} and Pedersen, {Anders Elm}",

year = "2013",

month = jul,

doi = "10.1097/mib.0b013e318286fa1c",

language = "English",

volume = "19",

pages = "1567--1576",

journal = "Inflammatory Bowel Diseases",

issn = "1078-0998",

publisher = "Lippincott Williams & Wilkins",

number = "8",

}

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 -

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

Abstract

Access to Document

Fingerprint

Cite this