多发性硬化症患者接受那他珠单抗治疗后对 JC 病毒的免疫应答：一项横断面和纵向研究。
Immune responses to JC virus in patients with multiple sclerosis treated with natalizumab: a cross-sectional and longitudinal study.
机构信息
Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
出版信息
Lancet Neurol. 2010 Mar;9(3):264-72. doi: 10.1016/S1474-4422(10)70006-5. Epub 2010 Jan 29.
BACKGROUND
Natalizumab is used to prevent relapses and progression of disability in patients with multiple sclerosis but has been associated with progressive multifocal leukoencephalopathy (PML). We aimed to better understand the associations between JC virus, which causes PML, and natalizumab treatment.
METHODS
We prospectively assessed patients with multiple sclerosis who started treatment with natalizumab. Blood and urine samples were tested for the presence of JC virus DNA with quantitative real-time PCR before treatment and at regular intervals after treatment onset for up to 18 months. At the same timepoints, by use of proliferation and enzyme-linked immunospot assays, the cellular immune responses against JC virus, Epstein-Barr virus, cytomegalovirus, myelin oligodendrocyte glycoprotein, and myelin oligodendrocyte basic protein (MOBP) were assessed. Humoral immune response specific to JC virus was assessed with an enzyme immunoassay. The same experiments were done on blood samples from patients with multiple sclerosis before and 10 months after the start of interferon beta treatment.
FINDINGS
We assessed 24 patients with multiple sclerosis who received natalizumab and 16 who received interferon beta. In patients treated with natalizumab, JC virus DNA was not detected in the blood at any timepoint. However, JC virus DNA was present in the urine of six patients and in most of these patients the concentrations of JC virus DNA were stable over time. Compared with pretreatment values, the cellular immune response was increased to cytomegalovirus at 6 months, to JC virus at 1, 9, and 12 months, and to Epstein-Barr virus and MOBP at 12 months. Humoral responses remained stable. There were no increases in cellular immune responses specific to the viruses or myelin proteins in the 16 patients treated with interferon beta.
INTERPRETATION
Natalizumab increases cellular immune responses specific to viruses and myelin proteins in the peripheral blood after 1 year, without evidence of viral reactivation.
FUNDING
Swiss National Foundation, Swiss Society for Multiple Sclerosis, and Biogen Dompé.
背景
那他珠单抗用于预防多发性硬化症患者的复发和残疾进展，但与进行性多灶性白质脑病（PML）有关。我们旨在更好地了解导致 PML 的 JC 病毒与那他珠单抗治疗之间的关联。
方法
我们前瞻性评估了开始接受那他珠单抗治疗的多发性硬化症患者。在治疗前和治疗开始后定期采集血液和尿液样本，通过实时定量 PCR 检测 JC 病毒 DNA 的存在，时间长达 18 个月。同时，通过增殖和酶联免疫斑点测定法评估针对 JC 病毒、EB 病毒、巨细胞病毒、髓鞘少突胶质细胞糖蛋白和髓鞘少突胶质细胞碱性蛋白（MOBP）的细胞免疫反应。通过酶免疫测定法评估针对 JC 病毒的体液免疫反应。对开始接受干扰素β治疗前和 10 个月后的多发性硬化症患者的血液样本进行了相同的实验。
结果
我们评估了 24 名接受那他珠单抗治疗和 16 名接受干扰素β治疗的多发性硬化症患者。在接受那他珠单抗治疗的患者中，任何时间点均未在血液中检测到 JC 病毒 DNA。然而，在 6 名患者的尿液中存在 JC 病毒 DNA，并且在大多数这些患者中，JC 病毒 DNA 的浓度随时间保持稳定。与治疗前相比，在 6 个月时对巨细胞病毒的细胞免疫反应增加，在 1、9 和 12 个月时对 JC 病毒的细胞免疫反应增加，在 12 个月时对 EB 病毒和 MOBP 的细胞免疫反应增加。体液反应保持稳定。在接受干扰素β治疗的 16 名患者中，没有针对病毒或髓鞘蛋白的细胞免疫反应增加。
解释
那他珠单抗在 1 年后增加外周血中针对病毒和髓鞘蛋白的细胞免疫反应，而没有病毒重新激活的证据。
资助
瑞士国家基金会、瑞士多发性硬化症学会和 Biogen Dompé。
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