Elsevier

Ophthalmology

Volume 125, Issue 12, December 2018, Pages 1977-1983
Ophthalmology

Translational Science Review
Targeting Interleukin-23 in the Treatment of Noninfectious Uveitis

https://doi.org/10.1016/j.ophtha.2018.05.014Get rights and content

The interleukin (IL)-23/IL-17 axis plays a central role in the pathogenesis of immune-mediated diseases such as psoriasis, psoriatic arthritis, Crohn’s disease, and uveitis. Therefore, targeting the IL-23/IL-17 axis has become the focus of multiple clinical trials for drug development in patients with autoimmune diseases. We briefly describe the biology of the IL-23/IL-17 axis and its relevance to the pathogenesis of experimental and clinical uveitis, and review the monoclonal antibody therapies targeting this pathway. Finally, 2 ongoing phase 2 trials of the anti–IL-23 biologic therapy ustekinumab (STELARA, Janssen Biotech Inc, Horsham, PA) in patients with noninfectious uveitis are introduced.

Section snippets

T-Helper 17 Cells in the Pathogenesis of Uveitis

At the center of the IL-23/IL-17 inflammatory axis lies the T-helper (Th) 17 cell.8 The Th17 cells are named for their signature cytokine, IL-17, which they produce in abundance once activated. T-helper 17 cells are an important subpopulation of CD4+ Th cells that were identified in 2005 and expanded the prior Th1 versus Th2 paradigm of Th cell subpopulations (reviewed in Tesmer et al9). T-helper 17 cells have been identified in the eyes of mice with EAU, and uveitis severity has been linked to

Interleukin-23 in Autoimmunity

The cytokine environment in which a naïve T-cell experiences its cognate antigen helps determine what type of T-cell will ultimately develop. Multiple lines of evidence point to IL-23 as the key checkpoint used by naïve T cells to make the decision whether to become a homeostatic Th17 or pathogenic Th17 effector cell.23, 30, 31 To begin Th17 differentiation, naïve T-cells require exposure to transforming growth factor-β and IL-6, and in the absence of these cytokines Th17 cells fail to develop.

Evidence for Interleukin-23 as a Mediator of Uveitis

In human studies, increased IL-23 has been found in the serum and the supernatants of peripheral blood mononuclear cells from patients with active Vogt–Koyonagi–Harada and Behçet's uveitis compared with patients with inactive uveitis and normal control subjects.21, 37, 38 Przepiera-Bedzak et al39 have shown that increased serum levels of IL-23 are associated with increased risk of acute anterior uveitis in patients with spondyloarthropathy (in addition to elevated IL-6, IL-18, and decreased

Clinical Trials and Agents Targeting the Interleukin-23/17 Axis

Biologic agents targeting the IL-23/IL-17 axis have been studied in inflammatory bowel disease, psoriasis, ankylosing spondylitis, and uveitis. Because of the proximal relationship of IL-23 and IL-17, initially these 2 cytokines were believed to be interchangeable as targets for autoimmune disease. However, initial clinical results found some surprising differences in therapeutic efficacy of anti–IL-17 and anti–IL-23 agents. Continuing studies into the complexity of type-17 cell biology and the

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    The goal is to provide authoritative and cutting-edge reviews of topical state-of-the-art basic research that is expected to have broad clinical impact in the next few years. This is primarily a “by invitation only” submission type, however, if you have suggestions for topics, please contact Marco A. Zarbin, MD, PhD ([email protected]) the Editor for this section.

    Financial Disclosure(s): The author(s) made the following disclosures: K.P.: Support Research to Prevent Blindness Career Development Award (New York, NY), The Alcon Research Institute Young Investigators Grant (Fort Worth, TX), and the National Institute of Health, NEI K08EY023998.

    P.L.: Supported National Eye Institute Grant K08 EY022948, a Collins Medical Trust Grant, Research to Prevent Blindness Career Development Award. The manuscript is supported by Core Grants P30 EY010572 and P30 EY01730 from the National Institute of Health (Bethesda, MD) and by unrestricted departmental funding from Research to Prevent Blindness (New York, NY).

    HUMAN SUBJECTS: No human or animal subjects were used in this review article.

    Author Contributions:

    Conception and design: Pepple, Lin

    Analysis and interpretation: Pepple, Lin

    Data collection: Pepple, Lin

    Obtained funding: Pepple, Lin

    Overall responsibility: Pepple, Lin

    K.P. and P.L. contributed equally to this work.

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