Development of a Transgenic Mouse Model with Immune Tolerance for Human Coagulation Factor VIIa

ABSTRACT Purpose 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 p...

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Published in:Pharmaceutical research 2013-11, Vol.30 (11), p.2855-2867
Main Authors: Lenk, Christine, Unterthurner, Sabine, Schuster, Maria, Weiller, Markus, Antoine, Gerhard, Malisauskas, Mantas, Scheiflinger, Friedrich, Schwarz, Hans-Peter, de la Rosa, Maurus, Reipert, Birgit M.
Format: Article
Language:English
Subjects:
Animals
Biochemistry
Biological and medical sciences
Biomedical and Life Sciences
Biomedical Engineering and Bioengineering
Biomedicine
CD8-Positive T-Lymphocytes - immunology
Coagulation
DNA, Complementary - genetics
Factor VIIa - genetics
Factor VIIa - immunology
Factor VIIa - therapeutic use
Female
Hematologic and hematopoietic diseases
Hemophilia
Humans
Immune Tolerance
Immunity, Innate
Immunoglobulin G - blood
Immunoglobulin G - immunology
Immunology
Male
Medical Law
Medical sciences
Mice
Mice, Inbred C57BL
Mice, Transgenic
Models, Animal
Pharmacology
Pharmacology. Drug treatments
Pharmacology/Toxicology
Pharmacy
Platelet diseases and coagulopathies
Proteins
Research Paper
Transgenes
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Summary:ABSTRACT Purpose 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.
ISSN:0724-8741
1573-904X
DOI:10.1007/s11095-013-1115-3