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

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 5

Anti–IL-23 therapy inhibits PLP epitope spreading and relapsing EAE.

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Anti–IL-23 therapy inhibits PLP epitope spreading and relapsing EAE. (A)...
(A) Average clinical score of mice treated with anti–IL-23p19 (clone MB490) or anti-p40 antibody on the day of EAE onset. The first antibody dose was given by the i.v. route at the first sign of clinical disease and the 2 subsequent doses by the s.c. route at days 7 and 14 after EAE onset. One of 3 experiments is shown. Disease relapse incidence and histopathology scores are shown in Table 3. Arrows indicate the day of initial mAb treatment (day of disease onset). (B) Epitope spreading was determined by analysis of DLN cells or purified CNS mononuclear cells for response to PLP139–151 or PLP178–191 on either the day of disease onset or during disease relapse. Purified CNS mononuclear cells from mice treated with anti–IL-23p19 or isotype control mAbs were stimulated for 4 days with PLP peptides then pulsed with 3[H] 16 hours before proliferation assay. Cells from 3 to 4 mice of each treatment group were pooled and cultured at indicated PLP peptide concentration in triplicate wells. Results from 1 of 2 experiments are shown.