title: Persistent neutralizing antibodies abolish the interferon beta bioavailability in MS patients.
abstract: BACKGROUND
  MxA is an antiviral protein exclusively induced by type I interferons (IFN) and some viruses, and MxA gene expression is one of the most appropriate markers for measuring the biologic activity of exogenous IFNbeta.
  
  
  METHODS
  A new quantitative-competitive PCR method was used to quantify MxA mRNA in peripheral blood mononuclear cells of 99 treatment-naïve and 92 IFNbeta-treated patients with MS (22 Avonex, 17 Betaferon, and 53 Rebif-22). Every 3 months, IFNbeta-induced neutralizing antibodies (NAb) were evaluated in sera using a cytopathic effect assay. Three categories of patients were identified: NAb negative (NAb-), persistent NAb positive (NAb+, >or=2 consecutive positive samples), and isolated NAb+ (one positive sample).
  
  
  RESULTS
  Treatment-naïve patients expressed detectable MxA mRNA levels (mean = 36 +/- 32 fg MxA/pg glyceraldehyde-3-phosphate dehydrogenase (GAPDH); range 1 to 160) and an upper normal threshold was established (mean + 3 SD = 132 fg MxA/pg GAPDH). IFNbeta-treated patients exhibited more than 11-fold higher levels (mean = 412 +/- 282 fg MxA/pg GAPDH; range 16 to 1,172). However, 17 patients did not exhibit an increase in MxA mRNA level; 15 of these 17 patients showed a concurrent Nab+ titer. Moreover, 13 were persistent NAb+. Isolated NAb+ patients did not show a decrease in bioavailability of IFNbeta (n = 9; mean = 567 +/- 366 fg MxA/pg GAPDH; range 83 to 1,120). In NAb- patients, bioavailability was comparable among the three different IFNbeta preparations 12 hours after injection.
  
  
  CONCLUSIONS
  During IFNbeta therapy, the presence of NAb reduced or abolished bioavailability in a relevant percentage of patients. These data could be important for the early detection of patients with MS who are not responsive to IFNbeta therapy.
authors.affiliation: Unità dipartimentale: Centro Riferimento Regionale Sclerosi Multipla (CReSM) and Neurobiologia Clinica, Ospedale Universitario S. Luigi Gonzaga, Orbassano, Torino, Italy. NSGLB@tin.it
authors.forename: A
authors.initials: A
authors.lastname: Bertolotto
authors.forename: F
authors.initials: F
authors.lastname: Gilli
authors.forename: A
authors.initials: A
authors.lastname: Sala
authors.forename: M
authors.initials: M
authors.lastname: Capobianco
authors.forename: S
authors.initials: S
authors.lastname: Malucchi
authors.forename: E
authors.initials: E
authors.lastname: Milano
authors.forename: F
authors.initials: F
authors.lastname: Melis
authors.forename: F
authors.initials: F
authors.lastname: Marnetto
authors.forename: R L P
authors.initials: RL
authors.lastname: Lindberg
authors.forename: R
authors.initials: R
authors.lastname: Bottero
authors.forename: A
authors.initials: A
authors.lastname: Di Sapio
authors.forename: M T
authors.initials: MT
authors.lastname: Giordana
mesh_terms: D000906:Antibodies / Q000097:blood*; D001682:Biological Availability; D019204:GTP-Binding Proteins / Q000235:genetics; D006801:Humans; D000068556:Interferon beta-1a; D000068576:Interferon beta-1b; D016899:Interferon-beta / Q000276:immunology* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D009103:Multiple Sclerosis / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D064547:Myxovirus Resistance Proteins; D016133:Polymerase Chain Reaction / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism; D012016:Reference Values
chemical_list: D000906:Antibodies; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D012333:RNA, Messenger; D000068576:Interferon beta-1b; D016899:Interferon-beta; D019204:GTP-Binding Proteins; D000068556:Interferon beta-1a