title: Development of a transgenic mouse model with immune tolerance for human coagulation factor VIIa.
abstract: OBJECTIVE
  Human factor VIIa (FVIIa) is commonly used as bypassing therapy to treat bleeding episodes in hemophilia patients with neutralizing antibodies to factors VIII (FVIII) or IX (FIX). There is a need for a suitable animal model to assess the immunogenicity of new FVIIa products during preclinical development. The aim of this study was the design of a novel transgenic mouse model with immune tolerance to human FVIIa.
  
  
  METHODS
  The model was generated by transgenic expression of human F7 cDNA. FVIIa-specific immune responses after treatment with human FVIIa were assessed by analyzing circulating antibodies, antibody producing plasma cells and CD4(+) T cells.
  
  
  RESULTS
  In contrast to wild-type mice, human FVII transgenic mice did not develop antibodies when treated with human FVIIa. The immune tolerance was specific and could be broken by application of human FVIIa together with a strong stimulus of the innate immune system. Break of tolerance was associated with increased numbers of pro-inflammatory FVIIa-specific CD4(+) T cells.
  
  
  CONCLUSIONS
  The new mouse model is suitable to study the influence of the innate immune system on maintenance and break of immune tolerance against FVIIa and could be used to assess the immunogenicity of new FVIIa products during pre-clinical development.
authors.affiliation: Baxter BioScience, Industriestrasse 67, 1220, Vienna, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Lenk
authors.forename: Sabine
authors.initials: S
authors.lastname: Unterthurner
authors.forename: Maria
authors.initials: M
authors.lastname: Schuster
authors.forename: Markus
authors.initials: M
authors.lastname: Weiller
authors.forename: Gerhard
authors.initials: G
authors.lastname: Antoine
authors.forename: Mantas
authors.initials: M
authors.lastname: Malisauskas
authors.forename: Friedrich
authors.initials: F
authors.lastname: Scheiflinger
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Schwarz
authors.forename: Maurus
authors.initials: M
authors.lastname: de la Rosa
authors.forename: Birgit M
authors.initials: BM
authors.lastname: Reipert
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018076:DNA, Complementary / Q000235:genetics; D015942:Factor VIIa / Q000235:genetics* / Q000276:immunology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007113:Immunity, Innate; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D019076:Transgenes
chemical_list: D018076:DNA, Complementary; D007074:Immunoglobulin G; D015942:Factor VIIa