Epstein-Barr virus (EBV) latent membrane protein-1-specific cytotoxic T lymphocytes targeting EBV-carrying natural killer cell malignancies
Epstein-Barr virus (EBV) latent membrane protein-1-specific cytotoxic T lymphocytes targeting EBV-carrying natural killer cell malignancies
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DOI：
10.1002/eji.200535485
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发表时间：
2006-03-01
影响因子：
5.4
通讯作者：
Kuzushima, K
中科院分区：
文献类型：
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作者：
Demachi-Okamura, A;Ito, Y;Kuzushima, K
EB病毒（EBV）编码的潜伏膜蛋白（LMP）1是一个潜在的目标，免疫治疗的一些比例的霍奇金病病例，鼻咽癌，EBV相关的自然杀伤（NK）/T淋巴瘤，和慢性活动性EBV感染（CAEBV）。由于不知道EBV感染的NK/T细胞是否对LMP 1特异性细胞毒性T淋巴细胞（CTL）的溶解敏感，我们在此测试了mRNA转导的抗原呈递细胞（APC）刺激罕见的LMP 1特异性CTL的能力。一个43个氨基酸的N-末端缺失突变体LMP 1（Delta LMP 1）可以有效地表达在树突状细胞和CD 40激活的B细胞的mRNA电穿孔。发现表达Delta LMP 1的APC刺激来自健康供体的LMP 1特异性CTL，并且CTL克隆识别由HLA-A*0206分子呈递的肽IIIIILIFI。加工和介绍的抗原肽证明依赖于表达的免疫蛋白酶体亚基，低分子量蛋白-7，证实了RNA干扰基因沉默。此外，来自患有CAEBV的患者的EBV感染的NK细胞系和来自具有增强的HLA-A*0206表达的NK淋巴瘤的另一个NK细胞系被CTL特异性裂解。总体而言，这些数据表明，靶向EBV相关NK淋巴瘤和CAEBV中的LMP 1的免疫疗法可能作为一种替代治疗方式。
Epstein-Barr virus (EBV)-encoded latent membrane protein (LMP) 1 is a potential target for immunotherapy of some proportion of Hodgkin's disease cases, nasopharyngeal carcinomas, EBV-associated natural killer (NK)/T lymphomas, and chronic active EBV infection (CAEBV). Since it is unknown whether EBV-infected NK/T cells are susceptible to lysis by LMPl-specific cytotoxic T lymphohcytes (CTL), we here tested the ability of mRNA-transduced antigen-presenting cells (APC) to stimulate rare LMP1-specific CTL. A 43-amino acid N-terminal deletion mutant LMP1 (Delta LMP1) could be efficiently expressed in dendritic cells and CD40-activated B cells upon mRNA electroporation. Delta LMP1-expressing APC were found to stimulate LMP1-specific CTL from a healthy donor and a CTL clone recognized a peptide, IIIILIIFI, presented by HLA-A*0206 molecules. Processing and presentation of the antigenic peptide proved dependent on expression of an immunoproteasome subunit, low-molecular-weight protein-7, as confirmed by RNA interference gene silencing. Furthermore, an EBV-infected NK cell line derived from a patient with CAEBV, and another from an NK lymphoma with enforced HLA-A*0206 expression, were specifically lysed by the CTL. Overall, these data suggest that immunotherapy targeting LMP1 in EBV-associated NK lymphomas and CAEBV might serve as an alternative treatment modality.