Neutralizing IL-23 is superior to blocking IL-17 in suppressing intestinal inflammation in a spontaneous murine colitis model

Wang, Ran, Hasnain, Sumaira Z., Tong, Hui, Das, Indrajit, Che-Hao Chen, Alice, Oancea, Iulia, Proctor, Martina, Florin, Timothy H., Eri, Rajaraman D. and McGuckin, Michael A. (2015) Neutralizing IL-23 is superior to blocking IL-17 in suppressing intestinal inflammation in a spontaneous murine colitis model. Inflammatory Bowel Diseases, 21 5: 973-984. doi:10.1097/MIB.0000000000000353


Author Wang, Ran
Hasnain, Sumaira Z.
Tong, Hui
Das, Indrajit
Che-Hao Chen, Alice
Oancea, Iulia
Proctor, Martina
Florin, Timothy H.
Eri, Rajaraman D.
McGuckin, Michael A.
Title Neutralizing IL-23 is superior to blocking IL-17 in suppressing intestinal inflammation in a spontaneous murine colitis model
Journal name Inflammatory Bowel Diseases   Check publisher's open access policy
ISSN 1536-4844
1078-0998
Publication date 2015-05
Year available 2015
Sub-type Article (original research)
DOI 10.1097/MIB.0000000000000353
Volume 21
Issue 5
Start page 973
End page 984
Total pages 12
Place of publication Philadelphia, PA United States
Publisher Lippincott Williams & Wilkins
Collection year 2016
Language eng
Formatted abstract
Background: IL-23/TH17 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/TH17 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 TH17-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 TH17 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.
Keyword Colitis
IL-17
IL-23
Inflammatory bowel disease
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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