The immunogenicity of platelet-derived FVIII in hemophilia A mice with or without preexisting anti-FVIII immunity. Blood 2016 Mar 10;127(10):1346-54
Date
12/17/2015Pubmed ID
26668132Pubmed Central ID
PMC4786841DOI
10.1182/blood-2015-08-662916Scopus ID
2-s2.0-84960904100 (requires institutional sign-in at Scopus site) 23 CitationsAbstract
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.
Author List
Chen Y, Schroeder JA, Chen J, Luo X, Baumgartner CK, Montgomery RR, Hu J, Shi QAuthors
Robert R. Montgomery MD Adjunct Professor in the Pediatrics department at Medical College of WisconsinQizhen Shi MD, PhD Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAutoantibodies
Blood Coagulation Factor Inhibitors
Blood Platelets
Factor VIII
Hemophilia A
Mice
Mice, Mutant Strains
Platelet Transfusion
