title: A genetic variant of the anti-apoptotic protein Akt predicts natalizumab-induced lymphocytosis and post-natalizumab multiple sclerosis reactivation.
abstract: BACKGROUND
  Multiple sclerosis (MS) patients discontinuing natalizumab treatment are at risk of disease reactivation. No clinical or surrogate parameters exist to identify patients at risk of post-natalizumab MS reactivation.
  
  
  OBJECTIVE
  To determine the role of natalizumab-induced lymphocytosis and of Akt polymorphisms in disease reactivation after natalizumab discontinuation.
  
  
  METHODS
  Peripheral leukocyte count and composition were monitored in 93 MS patients during natalizumab treatment, and in 56 of these subjects who discontinued the treatment. Genetic variants of the anti-apoptotic protein Akt were determined in all subjects because natalizumab modulates the apoptotic pathway and lymphocyte survival is regulated by the apoptotic cascade.
  
  
  RESULTS
  Natalizumab-induced peripheral lymphocytosis protected from post-natalizumab MS reactivation. Subjects who relapsed or had magnetic resonance imaging (MRI) worsening after treatment cessation, in fact, had milder peripheral lymphocyte increases during the treatment, largely caused by less marked T cell increase. Furthermore, subjects carrying a variant of the gene coding for Akt associated with reduced anti-apoptotic efficiency (rs2498804T) had lower lymphocytosis and higher risk of disease reactivation.
  
  
  CONCLUSIONS
  This study identified one functionally meaningful genetic variant within the Akt signaling pathway that is associated with both lymphocyte count and composition alterations during natalizumab treatment, and with the risk of disease reactivation after natalizumab discontinuation.
authors.affiliation: Clinica Neurologica, Università Tor Vergata, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rossi
authors.forename: Caterina
authors.initials: C
authors.lastname: Motta
authors.forename: Valeria
authors.initials: V
authors.lastname: Studer
authors.forename: Fabrizia
authors.initials: F
authors.lastname: Monteleone
authors.forename: Valentina
authors.initials: V
authors.lastname: De Chiara
authors.forename: Fabio
authors.initials: F
authors.lastname: Buttari
authors.forename: Francesca
authors.initials: F
authors.lastname: Barbieri
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
authors.forename: Luca
authors.initials: L
authors.lastname: Battistini
authors.forename: Gary
authors.initials: G
authors.lastname: Cutter
authors.forename: Olaf
authors.initials: O
authors.lastname: Stüve
authors.forename: Marco
authors.initials: M
authors.lastname: Salvetti
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D008218:Lymphocytosis / Q000139:chemically induced*; D008297:Male; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D000069442:Natalizumab; D020641:Polymorphism, Single Nucleotide; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D012008:Recurrence
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D007155:Immunologic Factors; D000069442:Natalizumab; D051057:Proto-Oncogene Proteins c-akt