title: Induction of partial immune tolerance to factor VIII through prior mucosal exposure to the factor VIII C2 domain.
abstract: BACKGROUND
  The development of anti-factor VIII (FVIII) neutralizing antibodies (inhibitors) is a significant obstacle to FVIII replacement therapy.
  
  
  OBJECTIVE
  As mucosal administration of an antigen may induce immune tolerance we have evaluated the efficacy of mucosal antigen exposure to achieve tolerance to FVIII.
  
  
  METHODS
  We investigated the effects of oral and nasal administration of the purified FVIII C2 domain (FVIII-C2) to FVIII-deficient BALB/c mice prior to FVIII protein challenge. Mice received oral or nasal doses of FVIII-C2, followed by a subcutaneous challenge of either FVIII-C2 or FVIII. The development of anti-FVIII inhibitors, cytokine production by splenocytes in vitro, and adoptive transfer assays were analyzed.
  
  
  CONCLUSIONS
  Mucosal administration of FVIII-C2 decreases the titer of anti-FVIII-C2 inhibitors after FVIII-C2 challenge, and decreases the percentage of FVIII-C2 specific antibodies after challenge with full-length FVIII. Tolerance induction to FVIII-C2 is associated with increased IL-10 production by splenocytes in vitro, and can be adoptively transferred to naïve mice. This study is the first to demonstrate that tolerance to the FVIII-C2 domain can be induced via the mucosal route. Based on these results, the potential use of FVIII-specific mucosal tolerance induction as an immunotherapy treatment for anti-FVIII inhibitor development warrants further investigation.
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.
authors.forename: F E
authors.initials: FE
authors.lastname: Rawle
authors.forename: K P
authors.initials: KP
authors.lastname: Pratt
authors.forename: A
authors.initials: A
authors.lastname: Labelle
authors.forename: H L
authors.initials: HL
authors.lastname: Weiner
authors.forename: C
authors.initials: C
authors.lastname: Hough
authors.forename: D
authors.initials: D
authors.lastname: Lillicrap
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005169:Factor VIII / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism* / Q000627:therapeutic use*; D005260:Female; D006467:Hemophilia A / Q000097:blood / Q000235:genetics; D007108:Immune Tolerance; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary; D013154:Spleen / Q000166:cytology; D013997:Time Factors
chemical_list: D016207:Cytokines; D005169:Factor VIII