Liu Zhensheng, Savoldo Barbara, Huls Helen, Lopez Teresita, Gee Adrian, Wilson Jeffery, Brenner Malcolm K, Heslop Helen E, Rooney Cliona M
Center for Cell and Gene Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Recent Results Cancer Res. 2002;159:123-33. doi: 10.1007/978-3-642-56352-2_15.
The Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPD) that occur in individuals immunosuppressed by solid organ transplant (SOT) or T cell-depleted stem cell transplantation (SCT) are unequivocally a result of T cell dysfunction. Reconstitution of "at-risk" patients with EBV-specific cytotoxic T lymphocyte (CTL) lines that have been reactivated and expanded in vitro, should prevent the development of post-transplant lymphoproliferative disease or treat pre-existing disease. We have provided over 125 infusions of donor-derived EBV-specific CTL to 60 recipients of T cell-depleted stem cells. As prophylaxis, infusions were safe and effective, as no patient developed EBV-LPD, in contrast to 11.5% of controls who did not receive CTL. The CTL-reconstituted cellular immune responses to EBV, persisted for up to 80 months following infusion and reduced the high virus load seen in about 12% of patients. CTL were also effective in two of three patients who received CTL as treatment for fulminant disease. SOT recipients are also good candidates for CTL therapy, but present problems not seen in bone marrow transplant recipients. First the CTL product must be autologous, since the majority of tumors are recipient-derived and allogeneic CTL are unlikely to survive in vivo. Second most patients continue to receive immunosuppressive drugs, which may compromise the function of infused CTL. Third, unlike SCT recipients SOT recipients do not have an empty niche for EBV-specific CTL. Finally, standard protocols are not effective in generating CTL from seronegative recipients of EBV-carrying organs, who are the patients most at risk for the development of EBV-LPD. For CTL to be an option for the management of EBV in these patients, a sensitive and specific assay for the prediction of high-risk patients is required as well as an effective method for the generation of EBV-specific CTL from seronegative recipients.
发生在实体器官移植（SOT）或T细胞耗竭的干细胞移植（SCT）导致免疫抑制个体中的爱泼斯坦-巴尔病毒（EBV）相关淋巴增殖性疾病（LPD）无疑是T细胞功能障碍的结果。用在体外重新激活和扩增的EBV特异性细胞毒性T淋巴细胞（CTL）系对“高危”患者进行重建，应能预防移植后淋巴增殖性疾病的发生或治疗已存在的疾病。我们已向60名T细胞耗竭的干细胞受者提供了超过125次供体来源的EBV特异性CTL输注。作为预防措施，输注是安全有效的，因为没有患者发生EBV-LPD，而未接受CTL的对照组中有11.5%的患者发生了该病。CTL重建的针对EBV的细胞免疫反应在输注后持续长达80个月，并降低了约12%患者中出现的高病毒载量。CTL对三名接受CTL治疗暴发性疾病的患者中的两名也有效。SOT受者也是CTL治疗的良好候选者，但存在骨髓移植受者中未见到的问题。首先，CTL产品必须是自体的，因为大多数肿瘤是受者来源的，而异基因CTL在体内不太可能存活。其次，大多数患者继续接受免疫抑制药物，这可能会损害输注的CTL的功能。第三，与SCT受者不同，SOT受者没有EBV特异性CTL的空龛位。最后，标准方案在从携带EBV器官的血清阴性受者中产生CTL方面无效，而这些受者是发生EBV-LPD风险最高的患者。要使CTL成为这些患者中EBV管理的一种选择，需要一种敏感且特异的检测方法来预测高危患者，以及一种从血清阴性受者中产生EBV特异性CTL的有效方法。
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