title: Maintenance and break of immune tolerance against human factor VIII in a new transgenic hemophilic mouse model.
abstract: Replacement of the missing factor VIII (FVIII) is the current standard of care for patients with hemophilia A. However, the short half-life of FVIII makes frequent treatment necessary. Current efforts focus on the development of longer-acting FVIII concentrates by introducing chemical and genetic modifications to the protein. Any modification of the FVIII protein, however, risks increasing its immunogenic potential to induce neutralizing antibodies (FVIII inhibitors), and this is one of the major complications in current therapy. It would be highly desirable to identify candidates with a high risk for increased immunogenicity before entering clinical development to minimize the risk of exposing patients to such altered FVIII proteins. In the present study, we describe a transgenic mouse line that expresses a human F8 cDNA. This mouse is immunologically tolerant to therapeutic doses of native human FVIII but is able to mount an antibody response when challenged with a modified FVIII protein that possesses altered immunogenic properties. In this situation, immunologic tolerance breaks down and antibodies develop that recognize both the modified and the native human FVIII. The applicability of this new model for preclinical immunogenicity assessment of new FVIII molecules and its potential use for basic research are discussed.
authors.affiliation: Baxter BioScience, Vienna, Austria.
authors.forename: Pauline M
authors.initials: PM
authors.lastname: van Helden
authors.forename: Sabine
authors.initials: S
authors.lastname: Unterthurner
authors.forename: Corinna
authors.initials: C
authors.lastname: Hermann
authors.forename: Maria
authors.initials: M
authors.lastname: Schuster
authors.forename: Rafi U
authors.initials: RU
authors.lastname: Ahmad
authors.forename: Alexandra N
authors.initials: AN
authors.lastname: Schiviz
authors.forename: Markus
authors.initials: M
authors.lastname: Weiller
authors.forename: Gerhard
authors.initials: G
authors.lastname: Antoine
authors.forename: Peter L
authors.initials: PL
authors.lastname: Turecek
authors.forename: Eva M
authors.initials: EM
authors.lastname: Muchitsch
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Schwarz
authors.forename: Birgit M
authors.initials: BM
authors.lastname: Reipert
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D005169:Factor VIII / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology*; D005260:Female; D006467:Hemophilia A / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics* / Q000502:physiology; D007156:Immunologic Memory / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D013045:Species Specificity
chemical_list: D005169:Factor VIII