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Cell Immunol. 2018 Mar;325:64-68. doi: 10.1016/j.cellimm.2018.01.008. Epub 2018 Jan 31.

Oxidation of factor VIII increases its immunogenicity in mice with severe hemophilia A.

Author information

1
INSERM, UMR S 1138, Centre de recherche des Cordeliers, Paris F-75006, France; Université Pierre et Marie Curie-Paris6, UMR S 1138, Centre de recherche des Cordeliers, Paris F-75006, France; Université Paris Descartes, UMR S 1138, Centre de recherche des Cordeliers, Paris F-75006, France.
2
Department of Haematology, Christian Medical College, Vellore, India.
3
INSERM, UMR S 1138, Centre de recherche des Cordeliers, Paris F-75006, France; Université Pierre et Marie Curie-Paris6, UMR S 1138, Centre de recherche des Cordeliers, Paris F-75006, France; Université Paris Descartes, UMR S 1138, Centre de recherche des Cordeliers, Paris F-75006, France. Electronic address: sebastien.lacroix-desmazes@crc.jussieu.fr.

Abstract

The development of antibodies against therapeutic factor VIII (FVIII) represents the major complication of replacement therapy in patients with severe hemophilia A. Amongst the environmental risk factors that influence the anti-FVIII immune response, the presence of active bleeding or hemarthrosis has been evoked. Endothelium damage is typically associated with the release of oxidative compounds. Here, we addressed whether oxidation contributes to FVIII immunogenicity. The control with N-acetyl cysteine of the oxidative status in FVIII-deficient mice, a model of severe hemophilia A, reduced the immune response to exogenous FVIII. Ex vivo exposure of therapeutic FVIII to HOCl induced a mild oxidation of the molecule as evidenced by the loss of free amines and resulted in increased FVIII immunogenicity in vivo when compared to native FVIII. The increased immunogenicity of oxidized FVIII was not reverted by treatment of mice with N-acetyl cysteine, and did not implicate an increased maturation of professional antigen-presenting cells. Our data document that oxidation influences the immunogenicity of therapeutic FVIII.

KEYWORDS:

FVIII immunogenicity; FVIII inhibitors; Hemophilia A; Oxidative stress

PMID:
29395036
DOI:
10.1016/j.cellimm.2018.01.008
[Indexed for MEDLINE]

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