title: Successful immune tolerance induction by FVIII in hemophilia A patients with inhibitor may occur without deletion of FVIII-specific T cells.
abstract: BACKGROUND
  The development of an inhibitor is the major complication facing patients with hemophilia A treated by administration of factor (F) VIII concentrates. Restoration of tolerance to FVIII can be achieved by prolonged administration of FVIII (immune tolerance induction, ITI). Although ITI has been used for more than 30years in patients with hemophilia A and inhibitor, its mechanism of action is still poorly understood.
  
  
  OBJECTIVE
  As administration of high doses of antigen can induce the apoptosis of the T cells recognizing the antigen, a potential mechanism of action of ITI may be the deletion of FVIII-specific T cells.
  
  
  METHODS
  We studied the CD4+ T-cell response to FVIII in five (one mild, one moderate and three severe) patients successfully desensitized by administration of FVIII and in control subjects.
  
  
  RESULTS
  Following repeated stimulation with autologous dendritic cells loaded with FVIII, FVIII-specific T oligoclonal cell lines were expanded from the blood of one of the successfully desensitized patients. The FVIII-specific T cells produced IL-5, IL-13 and IL-2. By contrast, FVIII-specific T-cell lines could not be derived from three patients with mild hemophilia A without inhibitor or from four normal control subjects.
  
  
  CONCLUSIONS
  These data represent the first analysis of the cellular mechanisms regulating the induction of tolerance to FVIII. They demonstrate that successful tolerance induction may occur without deletion of FVIII-specific T cells.
authors.affiliation: Service d'Hématologie Pédiatrique CHU Nord Place Victor Pauchet, Amiens Centre pour Hémophiles, AP-HP Hôpital de Bicêtre, Université Paris-XI, le Kremlin-Bicêtre, France.
authors.forename: B
authors.initials: B
authors.lastname: Pautard
authors.forename: R
authors.initials: R
authors.lastname: D'Oiron
authors.forename: V
authors.initials: V
authors.lastname: Li Thiao Te
authors.forename: R
authors.initials: R
authors.lastname: Lavend'homme
authors.forename: J-M
authors.initials: JM
authors.lastname: Saint-Remy
authors.forename: K
authors.initials: K
authors.lastname: Peerlinck
authors.forename: M
authors.initials: M
authors.lastname: Jacquemin
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018929:Cell Culture Techniques; D003713:Dendritic Cells / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005169:Factor VIII / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D006467:Hemophilia A / Q000150:complications* / Q000188:drug therapy / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007378:Interleukins / Q000096:biosynthesis; D037182:T-Cell Antigen Receptor Specificity
chemical_list: D007378:Interleukins; D005169:Factor VIII