| Author |
Wei, Lai Copland, David A. Dhanda, Ashwin D. Vistica, Barbara P. Jawad, Shayma Williams, Emily L. Lee, Richard W. J. Nussenblatt, Robert B. Wu, Wenting Schewitz-bowers, Lauren P. Chen, Ping Gery, Igal Liu, Baoying Tucker, William Li, Zhiyu Conway-campbell, Becky L. Sen, Nida Wakabayashi, Yoshiyuki Dick, Andrew D. Lait, Philippa J. P. Hirani, Sima Zhu, Jun |
| Description |
Author Affiliation: Schewitz-Bowers LP ( School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, Bristol BS8 1TD, United Kingdom); Lait PJ ( School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, Bristol BS8 1TD, United Kingdom); Copland DA ( School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, Bristol BS8 1TD, United Kingdom); Chen P ( Laboratory of Immunology, National Eye Institute.); Wu W ( Laboratory of Immunology, National Eye Institute.); Dhanda AD ( School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, Bristol BS8 1TD, United Kingdom); Vistica BP ( Laboratory of Immunology, National Eye Institute.); Williams EL ( School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, Bristol BS8 1TD, United Kingdom); Liu B ( Laboratory of Immunology, National Eye Institute.); Jawad S ( Laboratory of Immunology, National Eye Institute.); Li Z ( Laboratory of Immunology, National Eye Institute.); Tucker W ( Laboratory of Immunology, National Eye Institute.); Hirani S ( Laboratory of Immunology, National Eye Institute.); Wakabayashi Y ( Systems Biology Center, National Heart Lung Blood Institute, and.); Zhu J ( Systems Biology Center, National Heart Lung Blood Institute, and.); Sen N ( Laboratory of Immunology, National Eye Institute.); Conway-Campbell BL ( School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, Bristol BS8 1TD, United Kingdom); Gery I ( Laboratory of Immunology, National Eye Institute.); Dick AD ( School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, Bristol BS8 1TD, United Kingdom); Wei L ( Laboratory of Immunology, National Eye Institute, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.); Nussenblatt RB ( Laboratory of Immunology, National Eye Institute, Center for Human Immunology, Autoimmunity, and Inflammation, National Institutes of Health, Bethesda, MD 20892); Lee RW ( School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, Bristol BS8 1TD, United Kingdom); |
| Abstract |
Glucocorticoids remain the cornerstone of treatment for inflammatory conditions, but their utility is limited by a plethora of side effects. One of the key goals of immunotherapy across medical disciplines is to minimize patients' glucocorticoid use. Increasing evidence suggests that variations in the adaptive immune response play a critical role in defining the dose of glucocorticoids required to control an individual's disease, and Th17 cells are strong candidate drivers for nonresponsiveness [also called steroid resistance (SR)]. Here we use gene-expression profiling to further characterize the SR phenotype in T cells and show that Th17 cells generated from both SR and steroid-sensitive individuals exhibit restricted genome-wide responses to glucocorticoids in vitro, and that this is independent of glucocorticoid receptor translocation or isoform expression. In addition, we demonstrate, both in transgenic murine T cells in vitro and in an in vivo murine model of autoimmunity, that Th17 cells are reciprocally sensitive to suppression with the calcineurin inhibitor, cyclosporine A. This result was replicated in human Th17 cells in vitro, which were found to have a conversely large genome-wide shift in response to cyclosporine A. These observations suggest that the clinical efficacy of cyclosporine A in the treatment of SR diseases may be because of its selective attenuation of Th17 cells, and also that novel therapeutics, which target either Th17 cells themselves or the effector memory T-helper cell population from which they are derived, would be strong candidates for drug development in the context of SR inflammation. |
