Leflunomide/teriflunomide inhibit Epstein-barr virus (EBV)-induced lymphoproliferative disease and lytic viral replication

Andrea Bilger, Julie Plowshay, Shidong Ma, Dhananjay Nawandar, Elizabeth A. Barlow, James C. Romero-Masters, Jillian A. Bristol, Zhe Li, Ming Han Tsai, Henri Jacques Delecluse, Shannon C. Kenney*

*此作品的通信作者

研究成果: Article同行評審

59 引文 斯高帕斯(Scopus)

摘要

EBV infection causes mononucleosis and is associated with specific subsets of B cell lymphomas. Immunosuppressed patients such as organ transplant recipients are particularly susceptible to EBV-induced lymphoproliferative disease (LPD), which can be fatal. Leflunomide (a drug used to treat rheumatoid arthritis) and its active metabolite teriflunomide (used to treat multiple sclerosis) inhibit de novo pyrimidine synthesis by targeting the cellular dihydroorotate dehydrogenase, thereby decreasing T cell proliferation. Leflunomide also inhibits the replication of cytomegalovirus and BK virus via both "on target" and "off target" mechanisms and is increasingly used to treat these viruses in organ transplant recipients. However, whether leflunomide/teriflunomide block EBV replication or inhibit EBV-mediated B cell transformation is currently unknown. We show that teriflunomide inhibits cellular proliferation, and promotes apoptosis, in EBV-transformed B cells in vitro at a clinically relevant dose. In addition, teriflunomide prevents the development of EBV-induced lymphomas in both a humanized mouse model and a xenograft model. Furthermore, teriflunomide inhibits lytic EBV infection in vitro both by preventing the initial steps of lytic viral reactivation, and by blocking lytic viral DNA replication. Leflunomide/teriflunomide might therefore be clinically useful for preventing EBV-induced LPD in patients who have high EBV loads yet require continued immunosuppression.

原文English
頁(從 - 到)44266-44280
頁數15
期刊Oncotarget
8
發行號27
DOIs
出版狀態Published - 2017

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