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

J Clin Invest. 2006 May;116(5):1317-26. doi: 10.1172/JCI25308.

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*
  • Interleukins / metabolism
  • Interleukins / physiology*
  • Multiple Sclerosis / therapy*
  • STAT1 Transcription Factor / metabolism
  • T-Lymphocytes / immunology
  • Tumor Necrosis Factors / metabolism

Substances

  • 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