Activation of OX40 augments Th17 cytokine expression and antigen-specific uveitis

Zili Zhang, Wenwei Zhong, David Hinrichs, Xiumei Wu, Andrew Weinberg, Mark Hall, Doran Spencer, Keith Wegmann, James T. Rosenbaum

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22 Scopus citations

Abstract

Uveitis is a major and common cause of visual disability. Recent studies have shown that Th17 cells are implicated in the pathogenesis of this serious intraocular disorder. Activated T cells express an inducible costimulatory molecule called OX40, and OX40 in turn promotes the activation and proliferation of these lymphocytes. Nevertheless, it is unclear whether OX40 plays a vital role in enhancing the effector function of Th17 cells as well as the severity of uveitis. In this study, we demonstrated an increase of OX40 transcription in ovalbumin-induced uveitis, whereas anti-OX40L antibody substantially inhibited the antigen-specific ocular inflammation. Next, results from flow cytometry showed that activated Th17 cells expressed OX40, and OX40-activating antibody significantly augmented the production of Th17 cytokines in vitro. To validate the impact of OX40 in vivo, we stimulated ovalbumin-specific T cells with the OX40-activating antibody. Compared to donor cells without OX40 activation, adoptive transfer of OX40-stimulated lymphocytes elicited more severe ocular inflammation. Furthermore, an interleukin-17-neutralizing antibody attenuated OX40-mediated uveitis. In conclusion, our findings suggest that activation of OX40 augments Th17 cell function and thereby contributes to ocular inflammation. This study thus enhances our knowledge of costimulatory molecule-mediated immunopathological mechanisms of uveitis and suggests a future therapeutic strategy to treat uveitis by the targeting of OX40.

Original languageEnglish (US)
Pages (from-to)2912-2920
Number of pages9
JournalAmerican Journal of Pathology
Volume177
Issue number6
DOIs
StatePublished - Dec 2010

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Zhang, Z., Zhong, W., Hinrichs, D., Wu, X., Weinberg, A., Hall, M., Spencer, D., Wegmann, K., & Rosenbaum, J. T. (2010). Activation of OX40 augments Th17 cytokine expression and antigen-specific uveitis. American Journal of Pathology, 177(6), 2912-2920. https://doi.org/10.2353/ajpath.2010.100353