Targeted Activation of Human Vγ9Vδ2-T Cells Controls Epstein-Barr Virus-Induced B Cell Lymphoproliferative Disease
Targeted Activation of Human Vγ9Vδ2-T Cells Controls Epstein-Barr Virus-Induced B Cell Lymphoproliferative Disease
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DOI：
10.1016/j.ccr.2014.07.026
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发表时间：
2014-10-13
期刊：
影响因子：
50.3
通讯作者：
Tu, Wenwei
中科院分区：
文献类型：
--
作者：
Xiang, Zheng;Liu, Yinping;Tu, Wenwei
移植后 Epstein-Barr 病毒诱导的淋巴增殖性疾病（EBV-LPD）仍然是一种严重且危及生命的并发症。在此，我们表明，氨基二磷酸帕米膦酸扩增的人 V γ 9V δ 2-T 细胞通过 γ/δ-TCR 和 NKG2D 受体触发以及 Fas 和 TRAIL 接合，有效杀死 EBV 转化的自体淋巴母细胞 B 细胞系 (EBV-LCL)。通过将EBV-LCL接种到Rag2(-/-)gamma C-/-小鼠和人源化小鼠中，我们建立了与人类疾病特征接近的致死性EBV-LPD。单独过继转移帕米膦酸扩增的 V gamma 9V delta 2-T 细胞可有效预防 Rag2(-/-)gamma C-/- 小鼠中的 EBV-LPD，并诱导 EBV+ 荷瘤 Rag2-/-yc-/- 小鼠中的 EBV-LPD 消退。帕米膦酸钠治疗通过选择性激活和扩增 V gamma 9V delta 2-T 细胞抑制人源化小鼠中 EBV-LPD 的发育。这项研究为使用帕米膦酸盐通过 V gamma 9V delta 2-T 细胞靶向控制 EBV-LPD 的治疗方法提供了原理验证。
Epstein-Barr virus-induced lymphoproliferative disease (EBV-LPD) after transplantation remains a serious and life-threatening complication. Herein we showed that the aminobisphosphonate pamidronate-expanded human V gamma 9V delta 2-T cells efficiently killed EBV-transformed autologous lymphoblastoid B cell lines (EBV-LCL) through gamma/delta-TCR and NKG2D receptor triggering and Fas and TRAIL engagement. By inoculation of EBV-LCL in Rag2(-/-)gamma C-/- mice and humanized mice, we established lethal EBV-LPD with characteristics close to those of the human disease. Adoptive transfer of pamidronate-expanded V gamma 9V delta 2-T cells alone effectively prevented EBV-LPD in Rag2(-/-)gamma C-/- mice and induced EBV-LPD regression in EBV+ tumor-bearing Rag2-/-yc-/- mice. Pamidronate treatment inhibited EBV-LPD development in humanized mice through selective activation and expansion of V gamma 9V delta 2-T cells. This study provides proof-of-principle for a therapeutic approach using pamidronate to control EBV-LPD through V gamma 9V delta 2-T cell targeting.