title: A major determinant of the immunogenicity of factor VIII in a murine model is independent of its procoagulant function.
abstract: A main complication of treatment of patients with hemophilia A is the development of anti-factor VIII (fVIII) antibodies. The immunogenicity of fVIII potentially is a function of its procoagulant activity, which may result in danger signals that drive the immune response. Alternatively, intrinsic structural elements in fVIII may be particularly immunogenic. Finally, VWF, the carrier protein for fVIII in plasma, may play a role in immune recognition. We compared the immunogenicity of wild-type (wt) B domain-deleted fVIII and 2 inactive fVIII molecules, R372A/R1689A fVIII and V634M fVIII in fVIII(-/-) and fVIII(-/-)/VWF(-/-) mice. R372A/R1689A fVIII lacks proteolytic recognition sites and is not released from VWF. In contrast, V634M fVIII undergoes proteolytic cleavage and dissociation from VWF. No significant difference was observed in the immunogenicity of wt fVIII and V634M fVIII. R372A/R1689A fVIII was slightly less immunogenic in a subset of immunization regimens tested. High doses of wt fVIII were required to produce an immune response in fVIII(-/-)/VWF(-/-) mice. Our results indicate that a main component of the immune response to fVIII is independent of its procoagulant function, is both positively and negatively affected by its association with VWF, and may involve intrinsic elements of fVIII structure.
authors.affiliation: Aflac Cancer Center and Blood Disorders Center, Department of Pediatrics, Emory University, Atlanta, GA 30322, USA.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Meeks
authors.forename: Courtney L
authors.initials: CL
authors.lastname: Cox
authors.forename: John F
authors.initials: JF
authors.lastname: Healey
authors.forename: Ernest T
authors.initials: ET
authors.lastname: Parker
authors.forename: Bhavya S
authors.initials: BS
authors.lastname: Doshi
authors.forename: Bagirath
authors.initials: B
authors.lastname: Gangadharan
authors.forename: Rachel T
authors.initials: RT
authors.lastname: Barrow
authors.forename: Pete
authors.initials: P
authors.lastname: Lollar
mesh_terms: D000818:Animals; D000917:Antibody Formation; D001777:Blood Coagulation / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005169:Factor VIII / Q000276:immunology* / Q000502:physiology*; D015951:Factor Xa / Q000378:metabolism; D006467:Hemophilia A / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D050505:Mutant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D015539:Platelet Activation; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism; D014841:von Willebrand Factor / Q000276:immunology* / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; D011994:Recombinant Proteins; D014841:von Willebrand Factor; D005169:Factor VIII; D013917:Thrombin; D015951:Factor Xa