Immune responses to JC virus in patients with multiple sclerosis treated with natalizumab: a cross-sectional and longitudinal study

Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
The Lancet Neurology (Impact Factor: 21.82). 03/2010; 9(3):264-72. DOI: 10.1016/S1474-4422(10)70006-5
Source: PubMed

ABSTRACT 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.
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.
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.
Natalizumab increases cellular immune responses specific to viruses and myelin proteins in the peripheral blood after 1 year, without evidence of viral reactivation.
Swiss National Foundation, Swiss Society for Multiple Sclerosis, and Biogen Dompé.

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    • "Natalizumab increases the percentage of activated leukocytes producing pro-inflammatory cytokines, which has been attributed to sequestration of activated lymphocytes in the peripheral circulation [62, 63]. The CD4/CD8 ratio is reduced with long-term therapy [64], and serum immunoglobulin (Ig) M and IgG levels decrease significantly with continued therapy [65]. "
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    ABSTRACT: Multiple sclerosis (MS) is a life-long, potentially debilitating disease of the central nervous system (CNS). MS is considered to be an immune-mediated disease, and the presence of autoreactive peripheral lymphocytes in CNS compartments is believed to be critical in the process of demyelination and tissue damage in MS. Although MS is not currently a curable disease, several disease-modifying therapies (DMTs) are now available, or are in development. These DMTs are all thought to primarily suppress autoimmune activity within the CNS. Each therapy has its own mechanism of action (MoA) and, as a consequence, each has a different efficacy and safety profile. Neurologists can now select therapies on a more individual, patient-tailored basis, with the aim of maximizing potential for long-term efficacy without interruptions in treatment. The MoA and clinical profile of MS therapies are important considerations when making that choice or when switching therapies due to suboptimal disease response. This article therefore reviews the known and putative immunological MoAs alongside a summary of the clinical profile of therapies approved for relapsing forms of MS, and those in late-stage development, based on published data from pivotal randomized, controlled trials.
    CNS Drugs 04/2014; 28(6). DOI:10.1007/s40263-014-0160-8 · 4.38 Impact Factor
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    • "It has been reported that subclinical reactivation of JCV occurs frequently in natalizumab-treated patients and that viral shedding is associated with a transient drop in JCV-specific cellular immune responses,55 suggesting that monitoring JCV-specific T cell responses might be an interesting biomarker for risk of PML. However, neither the reduced T cell response nor viral reactivation in peripheral blood during treatment with natalizumab has been reproduced in other studies.56,57 "
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    ABSTRACT: Natalizumab was the first monoclonal antibody to be approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) based on its short-term efficacy and overall tolerability. However, the incidence of treatment-associated progressive multifocal leukoencephalopathy (PML), an infection of the brain caused by the John Cunningham virus, jeopardized this efficacious treatment from the beginning. Eight years after licensing of natalizumab, long-term studies confirm the considerable and sustained efficacy of natalizumab, although the PML complication still threatens one of the most successful treatments available for RRMS. During these years, considerable progress has been made in identification of risk factors that allow more effective management of PML risk. In addition, long-term studies to define better when to start or stop treatment and to optimize treatment strategies after cessation of natalizumab are ongoing, and hopefully will improve management and will allow natalizumab to remain as a valuable therapeutic option for patients with highly active RRMS.
    Patient Related Outcome Measures 04/2014; 5:25-33. DOI:10.2147/PROM.S41768
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    • "Consistent with other studies [24,25] the overall frequency of JCV viruria was 28% at baseline, and respectively 12%, 24%, 20% and 16% after 1, 6, 12, and 24, months of natalizumab treatment. JCV viruria was detected in at least one sample during follow-up in 11/24 (42%) cases (Table 1); no significant differences were observed in JCV viral load in urine (Log10 copies/ml) when baseline results (median: 5.54, IQR: 4.96-5.97) "
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    ABSTRACT: Background The use of natalizumab in multiple sclerosis (MS) may favour JC virus reactivation; this phenomenon is usually asymptomatic but can, albeit rarely, evolve into frank progressive multifocal leucoencephalopathy (PML). Methods JCV-specific CD8+ T lymphocytes were evaluated by flow cytometry over a 24-month period in 24 natalizumab-treated MS patients in whom JCV DNA was or was not detected in blood using quantitative real-time polymerase chain reaction; all these cases were asymptomatic. Results Perforin- and grazymes-containing VP-1-specific CD8+ T lymphocytes were reduced whereas CD107a-expressing cells were increased in JCV positive patients, suggesting an active degranulation of these cells; naïve CD8+ T lymphocytes were also decreased whereas memory cells were increased in patients in whom JCV reactivation was observed. Conclusion The presence of a CD8+ T lymphocyte-mediated effector immune response offers a greater insight into reactivation of JCV and its clinical sequelae, and may help the monitoring of patients on natalizumab therapy.
    Journal of Translational Medicine 12/2012; 10(1):248. DOI:10.1186/1479-5876-10-248 · 3.99 Impact Factor
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