title: Splenic marginal zone antigen-presenting cells are critical for the primary allo-immune response to therapeutic factor VIII in hemophilia A.
abstract: BACKGROUND
  Alloimmune responses to intravenously administered protein therapeutics are the most common cause of failure of replacement therapy in patients with defective levels of endogenous proteins. Such a situation is encountered in some patients with hemophilia A, who develop inhibitory anti-factor (F)VIII alloantibodies after administration of FVIII to treat hemorrhages.
  
  
  OBJECTIVE
  The nature of the secondary lymphoid organs involved in the initiation of immune responses to human therapeutic has not been studied. We therefore investigated this in the case of FVIII, a self-derived exogenous protein therapeutic.
  
  
  METHODS
  The distribution of intravenously administered FVIII was followed after FVIII-deficient mice were injected with radiolabeled FVIII and using immunohistochemistry. The role of the spleen and antigen-presenting cells (APC) in the onset of the anti-FVIII immune response was analyzed upon splenectomy or treatment of the mice with APC-depleting compounds.
  
  
  RESULTS
  FVIII preferentially accumulated in the spleen at the level of metallophilic macrophages in the marginal zone (MZ). Surgical removal of the spleen or selective in vivo depletion of macrophages and CD11c-positive CD8 alpha-negative dendritic cells resulted in a drastic reduction in anti-FVIII immune responses.
  
  
  CONCLUSIONS
  Using FVIII-deficient mice as a model for patients with hemophilia A, and human pro-coagulant FVIII as a model for immunogenic self-derived protein therapeutics, our results highlight the importance of the spleen and MZ APCs in the initiation of immune responses to protein therapeutics. Identification of the receptors implicated in retention of protein therapeutics in the MZ may pave the way towards novel strategies aimed at reducing their immunogenicity.
authors.affiliation: Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris 6, UMRS 872, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Navarrete
authors.forename: S
authors.initials: S
authors.lastname: Dasgupta
authors.forename: S
authors.initials: S
authors.lastname: Delignat
authors.forename: G
authors.initials: G
authors.lastname: Caligiuri
authors.forename: O D
authors.initials: OD
authors.lastname: Christophe
authors.forename: J
authors.initials: J
authors.lastname: Bayry
authors.forename: A
authors.initials: A
authors.lastname: Nicoletti
authors.forename: S V
authors.initials: SV
authors.lastname: Kaveri
authors.forename: S
authors.initials: S
authors.lastname: Lacroix-Desmazes
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D005169:Factor VIII / Q000276:immunology / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006467:Hemophilia A / Q000188:drug therapy / Q000276:immunology*; D007109:Immunity / Q000187:drug effects; D007518:Isoantibodies / Q000097:blood*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D013154:Spleen / Q000166:cytology / Q000276:immunology*; D013156:Splenectomy; D014018:Tissue Distribution
chemical_list: D007518:Isoantibodies; D005169:Factor VIII