Du Pasquier Renaud A, Kuroda Marcelo J, Zheng Yue, Jean-Jacques Jims, Letvin Norman L, Koralnik Igor J
Division of ViralPathogenesis Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Brain. 2004 Sep;127(Pt 9):1970-8. doi: 10.1093/brain/awh215. Epub 2004 Jun 23.
Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the CNS of immunosuppressed individuals caused by the polyomavirus JC (JCV). In previous studies, we showed that JCV-specific cytotoxic T lymphocytes (JCV-specific CTL) were associated with a favourable outcome in patients with PML. However, these CTL had been assessed in PML survivors more than 1 year after the onset of disease and we could not determine whether this immune response was only a surrogate marker for a general recovery of the patient's immune system or a causal factor in the patient's neurological improvement. In this study, we assessed the relationship between JCV-specific CTL detected early in the course of PML and the subsequent course of disease activity. We enrolled 26 patients with possible or proven PML, including 21 HIV+ patients, less than 10 months after the onset of their neurological symptoms (3.7 +/- 2.5 months, median +/- interquartile range). JCV-specific CTL were detected by either 51Cr release or tetramer staining assay. Patients were then followed prospectively and the clinical course of PML was determined. At the time of their first immune evaluation, we found that 15 patients had detectable JCV-specific CTL. HIV+ patients with JCV-specific CTL had a higher CD4+ T-cell count (215 +/- 103/microl) and a lower HIV viral load (144 +/- 431 copies/ml) than those without JCV-specific CTL (32 +/- 59/microl, P = 0.004 and 43 100 +/- 54 778 copies/ml, P = 0.01). Thirteen of these 15 patients with JCV-specific CTL developed clinically quiescent PML, while only two out of 11 without detectable CTL controlled their neurological disease. Therefore, the early detection of JCV-specific CTL had an 87% predictive value for subsequent control of PML, while the absence of such CTL had an 82% predictive value for subsequent active PML (P = 0.0009). Fifteen patients were evaluated less than 4 months after the onset of PML (1.9 +/- 1.3 months). Of nine patients with JCV-specific CTL, seven (78%) demonstrated subsequent control of disease, whereas six out of six (100%) without JCV-specific CTL developed progressive PML (P = 0.007). Two to ten CTL assays were performed on PBMC of 11 patients. Of these patients, one had an increase in JCV-specific CTL preceding a significant clinical improvement. In another patient with otherwise stable immune parameters, a decline in JCV-specific CTL preceded an exacerbation of PML. We conclude that JCV-specific CTL can be detected early in PML and can predict control of this disease. Fluctuations of JCV-specific CTL in the blood are associated with variation in disease manifestations. These results indicate that JCV-specific CTL are associated with the control of PML.
进行性多灶性白质脑病（PML）是一种由多瘤病毒JC（JCV）引起的、发生于免疫抑制个体中枢神经系统的致命性脱髓鞘疾病。在之前的研究中，我们发现JCV特异性细胞毒性T淋巴细胞（JCV特异性CTL）与PML患者的良好预后相关。然而，这些CTL是在疾病发作1年多后的PML幸存者中进行评估的，我们无法确定这种免疫反应仅仅是患者免疫系统全面恢复的替代标志物，还是患者神经功能改善的因果因素。在本研究中，我们评估了在PML病程早期检测到的JCV特异性CTL与疾病活动后续病程之间的关系。我们纳入了26例可能患有或已确诊PML的患者，其中包括21例HIV阳性患者，这些患者在出现神经症状后不到10个月（3.7±2.5个月，中位数±四分位间距）。通过51Cr释放试验或四聚体染色试验检测JCV特异性CTL。然后对患者进行前瞻性随访，并确定PML的临床病程。在首次免疫评估时，我们发现15例患者可检测到JCV特异性CTL。与没有JCV特异性CTL的HIV阳性患者相比（分别为32±59/μl，P = 0.004和43100±54778拷贝/ml，P = 0.01），具有JCV特异性CTL的HIV阳性患者CD4 + T细胞计数更高（215±103/μl），HIV病毒载量更低。这15例具有JCV特异性CTL的患者中有13例发展为临床静止性PML，而11例未检测到CTL的患者中只有2例控制了神经疾病。因此，早期检测到JCV特异性CTL对PML后续控制的预测价值为87%，而未检测到此类CTL对后续活动性PML的预测价值为82%（P = 0.0009）。15例患者在PML发作后不到4个月（1.9±1.3个月）接受了评估。在9例具有JCV特异性CTL的患者中，7例（占78%）随后疾病得到控制，而6例没有JCV特异性CTL的患者全部（占100%）发展为进行性PML（P = 0.007）。对11例患者的外周血单核细胞进行了2至10次CTL检测。在这些患者中，1例在临床显著改善之前JCV特异性CTL增加。在另1例免疫参数原本稳定的患者中，PML加重之前JCV特异性CTL下降。我们得出结论，JCV特异性CTL可在PML早期检测到，并可预测该病的控制情况。血液中JCV特异性CTL的波动与疾病表现的变化相关。这些结果表明JCV特异性CTL与PML的控制相关。
