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PMID: 16670771 Published · ppublish English Journal Article

Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis.

The Journal of clinical investigation ·Vol. 116 ·No. 5 ·2006-05-00 ·Pages 1317-26

Chen Y, Langrish CL, McKenzie B, Joyce-Shaikh B, Stumhofer JS, McClanahan T, Blumenschein W, Churakovsa T, Low J, Presta L, Hunter CA, Kastelein RA, Cua DJ

Abstract

IL-23 is a member of the IL-12 cytokine family that drives a highly pathogenic T cell population involved in the initiation of autoimmune diseases. We have shown that IL-23-dependent, pathogenic T cells produced IL-17 A, IL-17 F, IL-6, and TNF but not IFN-gamma or IL-4. We now show that T-bet and STAT1 transcription factors are not required for the initial production of IL-17. However, optimal IL-17 production in response to IL-23 stimulation appears to require the presence of T-bet. To explore the clinical efficacy of targeting the IL-23 immune pathway, we generated anti-IL-23p19-specific antibodies and tested to determine whether blocking IL-23 function can inhibit EAE, a preclinical animal model of human multiple sclerosis. Anti-IL-23p19 treatment reduced the serum level of IL-17 as well as CNS expression of IFN-gamma, IP-10, IL-17, IL-6, and TNF mRNA. In addition, therapeutic treatment with anti-IL-23p19 during active disease inhibited proteolipid protein (PLP) epitope spreading and prevented subsequent disease relapse. Thus, therapeutic targeting of IL-23 effectively inhibited multiple inflammatory pathways that are critical for driving CNS autoimmune inflammation.

MeSH Terms
Animals Autoimmune Diseases/therapy Chemokine CXCL10 Chemokines, CXC/metabolism Disease Models, Animal Encephalomyelitis/therapy Female Inflammation/pathology Interferon-gamma/metabolism Interleukin-17/metabolism Interleukin-23 Interleukin-23 Subunit p19 Interleukin-6/metabolism Interleukins/immunology,metabolism,physiology Multiple Sclerosis/therapy STAT1 Transcription Factor/metabolism T-Lymphocytes/immunology Tumor Necrosis Factors/metabolism
Chemicals
Chemokine CXCL10 Chemokines, CXC IL23A protein, human Interleukin-17 Interleukin-23 Interleukin-23 Subunit p19 Interleukin-6 Interleukins STAT1 Transcription Factor Tumor Necrosis Factors Interferon-gamma
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Chen Yi
Discovery Research, Schering-Plough Biopharma, Palo Alto, California 94304, USA.
Langrish Claire L
McKenzie Brent
Joyce-Shaikh Barbara
Stumhofer Jason S
McClanahan Terrill
Blumenschein Wendy
Churakovsa Tatyana
Low Justin
Presta Leonard
Hunter Christopher A
Kastelein Robert A
Cua Daniel J
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI25308
Published
2006-05-00
Pages
1317-26
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC1450386
Subset
IM
External Links
PubMed source DOI: 10.1172/JCI25308 PMC Full Text View journal details
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