Activation of OX40 Augments Th17 Cytokine Expression and Antigen-Specific Uveitis

• DOI: 10.2353/ajpath.2010.100353
• Publication Date: 2010-10-16T02:24:17Z
• Authors: Zili Zhang; Wenwei Zhong; David Hinrichs; Xiumei Wu; Andrew Weinberg; Mark Hall; Doran Spencer; Keith Wegmann; James T. Rosenbaum
• Keywords: Mice, Inbred BALB C; 0303 health sciences; Membrane Glycoproteins; Gene Expression; Cell Differentiation; OX40 Ligand; Receptors, OX40; Antibodies, Neutralizing; 3. Good health; Mice, Inbred C57BL; Uveitis; Epitopes; Mice; 03 medical and health sciences; Tumor Necrosis Factors; Animals; Cytokines; Th17 Cells; Tumor Necrosis Factor Inhibitors; Immunotherapy; Antigens; Cells, Cultured

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.