Immune responses to JC virus in patients with multiple sclerosis treated with natalizumab: a cross-sectional and longitudinal study
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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ABSTRACT: Therapeutic approaches to multiple sclerosis (MS) are based on altering the functions of the immune system, either by using broad immunosuppressive drugs used for transplantation rejection and rheumatology, or by modulating them more discreetly with beta interferon and synthetic amino-acid copolymers. These strategies are only partially successful, have important safety and tolerability limitations, and have shown to be mostly effective in earlier stages of the disease, in which acute relapses dominate the clinical picture. For progressive phenotypes of MS there are currently no effective therapeutic options. As very specific and potent immunosuppressive agents, monoclonal antibodies (mAbs) may offer considerable advantages over other therapies for MS. During the last decade, anti-a4 integrin natalizumab became the first approved mAb for treatment of relapsing MS, after convincingly demonstrating clinically significant effects on two large Phase 3 trials. Moreover, the concept of disease remission was introduced for the first time, to describe patients that show no signs of clinical or imaging markers of disease activity during therapy with natalizumab. Of the mAbs under development for MS, alemtuzumab and rituximab have also shown promising evidence of effectiveness, and potentially expanded the therapeutic horizon to reversal of disease progression in early relapsing patients, and progressive patients who previously had not been studied. However, the appearance of progressive multifocal leukoencephalopathy (PML) in natalizumab-treated MS patients, as well as in patients with lymphoma, lupus and rheumatoid arthritis treated with rituximab, and autoimmune-type complications in alemtuzumab-treated MS patients underlines the fact that extended efficacy comes with significant clinical risks. The challenge is then how best to utilize therapies that have evidently superior efficacy in a chronic disease of young adults, to obtain the best benefit-risk ratio, and how to monitor and prevent emergent safety concerns.mAbs 01/2010; 2(6):670-81. DOI:10.4161/mabs.2.6.13270 · 4.73 Impact Factor
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