title: Immune responses to JC virus in patients with multiple sclerosis treated with natalizumab: a cross-sectional and longitudinal study.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Natalizumab increases cellular immune responses specific to viruses and myelin proteins in the peripheral blood after 1 year, without evidence of viral reactivation.
  
  
  BACKGROUND
  Swiss National Foundation, Swiss Society for Multiple Sclerosis, and Biogen Dompé.
authors.affiliation: Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Samantha
authors.initials: S
authors.lastname: Jilek
authors.forename: Emilie
authors.initials: E
authors.lastname: Jaquiéry
authors.forename: Hans H
authors.initials: HH
authors.lastname: Hirsch
authors.forename: Andreas
authors.initials: A
authors.lastname: Lysandropoulos
authors.forename: Mathieu
authors.initials: M
authors.lastname: Canales
authors.forename: Laurence
authors.initials: L
authors.lastname: Guignard
authors.forename: Myriam
authors.initials: M
authors.lastname: Schluep
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pantaleo
authors.forename: Renaud A
authors.initials: RA
authors.lastname: Du Pasquier
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D007577:JC Virus / Q000276:immunology*; D007968:Leukoencephalopathy, Progressive Multifocal / Q000139:chemically induced / Q000276:immunology / Q000821:virology; D008137:Longitudinal Studies; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology* / Q000821:virology; D000069442:Natalizumab; D011446:Prospective Studies
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000069442:Natalizumab