TY - JOUR
T1 - Activation of OX40 augments Th17 cytokine expression and antigen-specific uveitis
AU - Zhang, Zili
AU - Zhong, Wenwei
AU - Hinrichs, David
AU - Wu, Xiumei
AU - Weinberg, Andrew
AU - Hall, Mark
AU - Spencer, Doran
AU - Wegmann, Keith
AU - Rosenbaum, James T.
N1 - Funding Information:
Supported by National Institutes of Health grants EY016788 (Z.Z.), EY013093 (J.T.R.), and EY006484 (J.T.R.); and a CDHNF Young Investigator Award (Z.Z.). Funds from the Stan and Madelle Rosenfeld Family Trust, the William and Mary Bauman Foundation, Research to Prevent Blindness and William C. Kuzell Foundation also supported this work.
PY - 2010/12
Y1 - 2010/12
N2 - 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.
AB - 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.
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U2 - 10.2353/ajpath.2010.100353
DO - 10.2353/ajpath.2010.100353
M3 - Article
C2 - 20952591
AN - SCOPUS:78650202203
SN - 0002-9440
VL - 177
SP - 2912
EP - 2920
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 6
ER -