Characterization of antibodies induced by human factor VIII in a murine knockout model of hemophilia A

To investigate the usefulness of factor VIII (FVIII) knockout mice as an an imal-model of hemophilia A, we characterized the antibody response in FVIII knockout mice to recombinant human FVIII, administered intravenously or su bcutaneously with or without adjuvant, and compared results to those in nor mal mice. Anti-factor VIII antibodies were detected after both intravenous and subcutaneous administration, with the highest titers after subcutaneous administration plus adjuvant. Depending on the administration strategy, kn ockout mice formed antibodies more rapidly and developed higher titers of i nhibitory antibodies (Bethesda) than normal mice, suggesting differences in epitope specificity. Blotting thrombin cleavage products separated by gel electrophoresis showed that both strains developed antibodies against the n onfunctional B domain as well as against functional domains of factor VIII. The antibodies were mainly of the IgGl subclass and resembled type I antib odies in hemophilia A.