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标题：Glucocorticoid-resistant Th17 cells are selectively attenuated by cyclosporine A
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作者：Lauren P. Schewitz-Bowers ; Philippa J. P. Lait ; David A. Copland 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：13
页码：4080-4085
DOI：10.1073/pnas.1418316112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceCyclosporine A was one of the first drugs used in clinical practice to successfully rescue glucocorticoid-resistant inflammatory diseases. In this article we extend the characterization of glucocorticoid-resistant human Th17 cells, and demonstrate that this effector memory T-cell subset is reciprocally attenuated by cyclosporine A. This therapeutic paradigm was confirmed in a murine model of autoimmunity, refining our understanding of cyclosporine A's effect on the adaptive immune response. These data support the rationale for Th17-targeting therapies in the treatment of glucocorticoid-resistant inflammation. 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.
关键词：Th17 ; glucocorticoid ; steroid resistance ; calcineurin inhibition ; uveitis