Asymptomatic Reactivation of JC Virus in Patients Treated with Natalizumab
Asymptomatic Reactivation of JC Virus in Patients Treated with Natalizumab
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DOI：
10.1056/nejmoa0904267
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发表时间：
2009-09-10
影响因子：
158.5
通讯作者：
Koralnik, Igor J.
中科院分区：
文献类型：
--
作者：
Chen, Yiping;Bord, Evelyn;Koralnik, Igor J.
进展性多灶性白质脑病（PML）发生在一小部分接受那他珠单抗治疗的多发性硬化症患者中。大多数感染JC病毒（PML的病原体）的成年人没有症状。我们试图确定是否暴露于那他珠单抗导致亚临床再激活和嗜神经性转化的JC virus.METHODSWe随后连续19例多发性硬化症患者谁与那他珠单抗治疗超过18个月的时间，进行定量聚合酶链反应测定在血液和尿液中的JC病毒再激活; BK病毒，JC病毒相关的多瘤病毒，被用作对照。我们通过酶联免疫斑点试验和酶联免疫吸附试验测定JC病毒特异性T细胞应答，并分析JC病毒调节区序列。结果那他珠单抗治疗12个月后，19名患者尿液中JC病毒的患病率从基线值19%增加到63%（P = 0.02）。治疗18个月后，JC病毒在15个可用的血浆样本中的3个（20%）和15个可用的外周血单核细胞样本中的9个（60%）中可检测到（P = 0.02）。血液样本和大多数尿液样本中的JC病毒调节区序列与通常在PML中发现的序列相似。相反，BK病毒在尿液中保持稳定，在血液中检测不到。JC病毒特异性细胞免疫应答在治疗6至12个月之间显著下降，并且在JC病毒血症患者中，细胞免疫应答随时间的变化往往更大。没有一个患者有临床或放射学症状的PML. CONCLUSIONSSJC病毒亚临床再激活发生频繁那他珠单抗治疗的多发性硬化症患者。病毒脱落与JC病毒特异性细胞免疫应答的短暂下降相关。
BACKGROUNDProgressive multifocal leukoencephalopathy (PML) occurs in a fraction of patients with multiple sclerosis who were treated with natalizumab. Most adults who are infected with the JC virus, the etiologic agent in PML, do not have symptoms. We sought to determine whether exposure to natalizumab causes subclinical reactivation and neurotropic transformation of JC virus.METHODSWe followed 19 consecutive patients with multiple sclerosis who were treated with natalizumab over an 18-month period, performing quantitative polymerase-chainreaction assays in blood and urine for JC virus reactivation; BK virus, a JC virus-related polyomavirus, was used as a control. We determined JC virus-specific T-cell responses by means of an enzyme-linked immunospot assay and antibody responses by means of an enzyme-linked immunosorbent assay and analyzed JC virus regulatory-region sequences.RESULTSAfter 12 months of natalizumab therapy, the prevalence of JC virus in the urine of the 19 patients increased from a baseline value of 19% to 63% (P = 0.02). After 18 months of treatment, JC virus was detectable in 3 of 15 available plasma samples (20%) and in 9 of 15 available samples of peripheral-blood mononuclear cells (60%) (P = 0.02). JC virus regulatory-region sequences in blood samples and in most of the urine samples were similar to those usually found in PML. Conversely, BK virus remained stable in urine and was undetectable in blood. The JC virus-specific cellular immune response dropped significantly between 6 and 12 months of treatment, and variations in the cellular immune response over time tended to be greater in patients in whom JC viremia developed. None of the patients had clinical or radiologic signs of PML.CONCLUSIONSSubclinical reactivation of JC virus occurs frequently in natalizumab-treated patients with multiple sclerosis. Viral shedding is associated with a transient drop in the JC virus-specific cellular immune response.