Generation of Epstein-Barr virus-specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus (FK506)
Generation of Epstein-Barr virus-specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus (FK506)
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DOI：
10.1182/blood-2009-07-230482
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发表时间：
2009-11-26
期刊：
影响因子：
20.3
通讯作者：
Savoldo, Barbara
中科院分区：
文献类型：
--
作者：
De Angelis, Biagio;Dotti, Gianpietro;Savoldo, Barbara
自体EB病毒特异性细胞毒性T淋巴细胞（EBV-CTL）连续转移到实体器官移植（SOT）受者已被证明是安全和有效的治疗EB病毒相关的移植后淋巴组织增生性疾病（PTLD）。然而，SOT接受者需要持续给予免疫抑制药物以防止移植物排斥，并且这些药物可能显著限制转移的EBV-CTL的长期持续性，从而排除了它们作为预防的用途。他克莫司（FK 506）是SOT受者中最广泛使用的免疫抑制剂之一，其免疫抑制作用在很大程度上取决于其与12-kDa FK 506结合蛋白（FKBP 12）的相互作用。我们使用从逆转录病毒载体稳定表达的特异性小干扰RNA（siRNA）敲低了EBV-CTL中FKBP 12的表达，并发现FKBP 12沉默的EBV-CTL对FK 506具有抗性。这些细胞在药物存在下继续扩增，而其抗原特异性或细胞毒活性没有可测量的损害。我们使用异种小鼠模型证实了它们的FK 506耐药性和体内抗PTLD活性，这表明所提出的策略可能对增强移植后PTLD高风险患者的EBV特异性免疫监视具有价值。（血。2009; 114：4784-4791）
Adoptive transfer of autologous Epstein-Barr virus-specific cytotoxic T lymphocytes (EBV-CTLs) to solid organ transplant ( SOT) recipients has been shown safe and effective for the treatment of EBV-associated posttransplantation lymphoproliferative disorders (PTLDs). SOT recipients, however, require the continuous administration of immunosuppressive drugs to prevent graft rejection, and these agents may significantly limit the long-term persistence of transferred EBV-CTLs, precluding their use as prophylaxis. Tacrolimus (FK506) is one of the most widely used immunosuppressive agents in SOT recipients, and its immunosuppressive effects are largely dependent on its interaction with the 12-kDa FK506-binding protein (FKBP12). We have knocked down the expression of FKBP12 in EBV-CTLs using a specific small interfering RNA( siRNA) stably expressed from a retroviral vector and found that FKBP12-silenced EBV-CTLs are FK506 resistant. These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity. We confirmed their FK506 resistance and anti-PTLD activity in vivo using a xenogenic mouse model, suggesting that the proposed strategy may be of value to enhance EBV-specific immune surveillance in patients at high risk of PTLD after transplantation. (Blood. 2009; 114:4784-4791)