Wang, R and Hasnain, SZ and Tong, H and Das, I and Che-Hao Chen, A and Oancea, I and Proctor, M and Florin, TH and Eri, RD and McGukin, MA, Neutralizing IL-23 is superior to blocking IL-17 in suppressing intestinal inflammation in a spontaneous murine colitis model, Inflammatory Bowel Diseases, 21, (5) pp. 973-84. ISSN 1078-0998 (2015) [Refereed Article]
Copyright 2015 Crohn’s & Colitis Foundation of America, Inc.
Official URL: http://www.ncbi.nlm.nih.gov/pubmed/25803508
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.
|Item Type:||Refereed Article|
|Keywords:||IBD, IL-23, IL-17, colitis, inflammatory bowel disease|
|Research Division:||Biological Sciences|
|Research Field:||Genetic Immunology|
|Objective Group:||Clinical Health (Organs, Diseases and Abnormal Conditions)|
|Objective Field:||Digestive System Disorders|
|UTAS Author:||Eri, RD (Associate Professor Raj Eri)|
|Funding Support:||National Health and Medical Research Council (604304)|
|Web of Science® Times Cited:||16|
|Deposited By:||Health Sciences|
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