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Anti–IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis
Yi Chen, … , Robert A. Kastelein, Daniel J. Cua
Yi Chen, … , Robert A. Kastelein, Daniel J. Cua
Published May 1, 2006
Citation Information: J Clin Invest. 2006;116(5):1317-1326. https://doi.org/10.1172/JCI25308.
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Research Article Autoimmunity

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

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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-17A, IL-17F, IL-6, and TNF but not IFN-γ 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-γ, 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.

Authors

Yi Chen, Claire L. Langrish, Brent Mckenzie, Barbara Joyce-Shaikh, Jason S. Stumhofer, Terrill McClanahan, Wendy Blumenschein, Tatyana Churakovsa, Justin Low, Leonard Presta, Christopher A. Hunter, Robert A. Kastelein, Daniel J. Cua

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Figure 1

Anti–IL-23 treatment inhibits acute EAE.

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Anti–IL-23 treatment inhibits acute EAE.
(A) Average clinical score of m...
(A) Average clinical score of mice treated with 1 mg of anti–IL-23p19 (clone MB74) or anti–IL12p40 (clone C17.8) injected at day –1 and day 6 of EAE priming. One of 4 experiments is shown. Disease incidence and average disease onset of all mice are shown in Table 1. (B) Routine H&E histology of spinal cords from antibody-treated mice taken at days 30–40 of immunization. Original magnification, ×200. Representative micrographs of anti–IL-23p19 and -p40 treated groups show no inflammation in the white matter of the CNS. Rat IgG2a (rIgG2a) isotype control group shows infiltration of inflammatory cells in the lumbar region of the spinal cord. Mouse IgG1 (mIgG1) controls showed similar levels of CNS inflammatory cellular infiltration (not shown).
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