title: Neutralizing IL-23 is superior to blocking IL-17 in suppressing intestinal inflammation in a spontaneous murine colitis model.
abstract: BACKGROUND
  IL-23/T(H)17 inflammatory responses are regarded as central to the pathogenesis of inflammatory bowel disease, but clinically IL-17A antibodies have shown low efficacy and increased infections in Crohn's disease. Hence, we decided to closely examine the role of the IL-23/T(H)17 axis in 3 models of colitis.
  
  
  METHODS
  IL-17A(-/-) and IL-17Ra(-/-) T cells were transferred into Rag1 and RaW mice to assess the role of IL-17A-IL-17Ra signaling in T cells during colitis. In Winnie mice with spontaneous colitis due to an epithelial defect, we studied the progression of colitis in the absence of IL-17A and the efficacy of neutralizing antibodies against the IL-17A or IL-23p19 cytokines.
  
  
  RESULTS
  In transfer colitis models, IL-17A-deficient T cells failed to ameliorate disease, and IL-17Ra-deficient T cells were more colitogenic than wild-type T cells. In Winnie mice with an epithelial defect and spontaneous T(H)17-dominated inflammation, genetic deficiency of IL-17A did not suppress initiation of colitis but limited colitis progression. Furthermore, inhibition of IL-17A by monoclonal antibodies did not reduce colitis severity. In contrast, neutralizing IL-23 using an anti-p19 antibody significantly alleviated both emerging and established colitis, downregulating T(H)17 proinflammatory cytokine expression and diminishing neutrophil infiltration.
  
  
  CONCLUSIONS
  Our results support clinical studies showing that IL-17 neutralization is not therapeutic but that targeting IL-23 suppresses intestinal inflammation. Effects of IL-23 distinct from its effects on maturation of IL-17A-producing lymphocytes may underlie the protection from inflammatory bowel disease conveyed by hypomorphic IL-23 receptor polymorphisms and contribute to the efficacy of IL-23 neutralizing antibodies in inflammatory bowel disease.
authors: *Immunity, Infection and Inflammation Program, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba, Australia; †School of Biomedical Sciences and School of Medicine, University of Queensland, Brisbane, Australia; ‡School of Biomolecular and Physical Sciences, Griffith University, Nathan, Australia; and §School of Human Life Sciences, University of Tasmania, Launceston, Australia.
authors: Ran
authors: R
authors: Wang
authors: Sumaira Z
authors: SZ
authors: Hasnain
authors: Hui
authors: H
authors: Tong
authors: Indrajit
authors: I
authors: Das
authors: Alice
authors: A
authors: Che-Hao Chen
authors: Iulia
authors: I
authors: Oancea
authors: Martina
authors: M
authors: Proctor
authors: Timothy H
authors: TH
authors: Florin
authors: Rajaraman D
authors: RD
authors: Eri
authors: Michael A
authors: MA
authors: McGuckin
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003092:Colitis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D053759:Interleukin-23 / Q000037:antagonists & inhibitors*; D007422:Intestines / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016207:Cytokines; C098680:Il17a protein, mouse; D020381:Interleukin-17; D053759:Interleukin-23; D012333:RNA, Messenger