title: The immunogenicity of platelet-derived FVIII in hemophilia A mice with or without preexisting anti-FVIII immunity.
abstract: Evidence shows that factor VIII (FVIII) ectopically expressed in platelets (2bF8) is therapeutic in FVIII(null) mice even with anti-FVIII inhibitory antibodies (inhibitors). If current efforts to generate platelets in vitro succeed, genetically manipulated platelets containing FVIII may be used therapeutically in hemophilia A patients with inhibitors. One important concern is the immunogenicity of platelet-derived FVIII. To address this concern, we infused 2bF8 transgenic (2bF8(Tg)) platelets into naïve FVIII(null) mice weekly for 8 weeks. No anti-FVIII antibodies were detected in the infused animals during the study course. We then explored whether platelet-derived FVIII is immunogenic in FVIII(null) mice with inhibitors. The 2bF8(Tg) platelets were transfused into rhF8-primed FVIII(null) mice, resulting in no augmentation of anti-FVIII antibodies. To investigate whether preconditioning affects the immune response, animals were sublethally irradiated and subsequently transfused with 2bF8(Tg) platelets. No anti-FVIII antibodies were detected in the recipients after platelet infusions. Following further challenge with rhF8, the inhibitor titer in this group was significantly lower than in naïve FVIII(null) mice utilizing the same immunization protocol. Thus, our data demonstrate that infusion of platelets containing FVIII triggers neither primary nor memory anti-FVIII immune response in FVIII(null) mice and that sublethal irradiation plus 2bF8(Tg) platelet infusion suppresses anti-FVIII immune response in FVIII(null) mice.
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; Fujian Institute of Hematology, Fujian Medical University Union Hospital, Fuzhou, China;
authors.forename: Yingyu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI;
authors.forename: Jocelyn A
authors.initials: JA
authors.lastname: Schroeder
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI;
authors.forename: Juan
authors.initials: J
authors.lastname: Chen
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; Fujian Institute of Hematology, Fujian Medical University Union Hospital, Fuzhou, China;
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Luo
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI;
authors.forename: Christina K
authors.initials: CK
authors.lastname: Baumgartner
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI; Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, WI; and.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Montgomery
authors.affiliation: Fujian Institute of Hematology, Fujian Medical University Union Hospital, Fuzhou, China;
authors.forename: Jianda
authors.initials: J
authors.lastname: Hu
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI; Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, WI; and Midwest Athletes Against Childhood Cancer Research Center, Milwaukee, WI.
authors.forename: Qizhen
authors.initials: Q
authors.lastname: Shi
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D019774:Blood Coagulation Factor Inhibitors / Q000276:immunology*; D001792:Blood Platelets / Q000276:immunology*; D005169:Factor VIII / Q000235:genetics / Q000276:immunology*; D006467:Hemophilia A / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D017713:Platelet Transfusion
chemical_list: D001323:Autoantibodies; D019774:Blood Coagulation Factor Inhibitors; D005169:Factor VIII