Anti–IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis
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
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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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 4

T-bet and TIM3 expression in IFN-γ– and IL-17–producing T cells.

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T-bet and TIM3 expression in IFN-γ– and IL-17–producing T cells. (A) Lym...
(A) Lymph node cells from naive C57BL/6 WT mice and T-bet– or STAT1-deficient mice were stimulated with soluble anti-CD3 for 48 hours in the presence or absence of IL-23. IL-17 levels in the culture supernatant were measured by ELISA. Data are mean cytokine production ± SD of separate lymph node cultures from 3 mice and are representative of 3 independent experiments. (B) SJL mice were immunized with PLP139–151, and DLN cells were cultured with 20 μg/ml PLP peptide either in Th1-promoting conditions (IL-12 with blocking anti–IL-17 and anti–IL-23p19) or Th17-promoting conditions (IL-23 with blocking anti–IFN-γ and anti–IL-12p35). Cells were collected at 0, 4, 12, 24, 48, 72, 96, and 120 hours after culture. mRNA for T-bet was quantified by real-time PCR (TaqMan) and normalized to ubiquitin. Data are representative of 3 independent experiments. (C) At 96 hours, IL-17– and IFN-γ–producing CD4+ T cells were identified by intracellular cytokine staining. T-bet and TIM3 expression were determined by costaining of cytokine-positive cells for T-bet (clone 4B10) or TIM3 (clone 8B.2C12).