1. Downregulation of CD40 signal and induction of TGF-β by phosphatidylinositol mediates reduction in immunogenicity against recombinant human Factor VIII.
- Author
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Gaitonde P, Peng A, Straubinger RM, Bankert RB, and Balu-Iyer SV
- Subjects
- Animals, Antibodies, Neutralizing immunology, Antigen-Presenting Cells drug effects, Antigen-Presenting Cells metabolism, CD40 Antigens immunology, Cells, Cultured, Dendritic Cells drug effects, Dendritic Cells metabolism, Down-Regulation drug effects, Down-Regulation immunology, Factor VIII metabolism, Humans, Interleukins metabolism, Mice, Mice, Inbred C57BL, Nanoparticles administration & dosage, Recombinant Proteins immunology, Recombinant Proteins pharmacology, T-Lymphocytes drug effects, T-Lymphocytes immunology, T-Lymphocytes metabolism, Transforming Growth Factor beta1 immunology, Up-Regulation drug effects, Up-Regulation immunology, CD40 Antigens metabolism, Dendritic Cells immunology, Factor VIII immunology, Factor VIII pharmacology, Phosphatidylinositols immunology, Phosphatidylinositols pharmacology, Transforming Growth Factor beta1 metabolism
- Abstract
Factor VIII (FVIII) is an important coagulation cofactor and its deficiency causes Hemophilia A, a bleeding disorder. Replacement therapy using recombinant FVIII is currently the first line of therapy for Hemophilia A, but the development of neutralizing antibody is a major clinical complication for this therapy. Recently, it has been shown that FVIII associated with phosphatidylinositol (PI)-containing lipidic nanoparticles reduced development of neutralizing antibodies in Hemophilia A mice (Peng A, Straubinger RM, Balu-Iyer SV. 2010. AAPS J 12(3):473-481). Here, we investigated the underlying mechanism of this reduction in antibody response in culturing conditions. In vitro, PI interfered with the processing of FVIII by cultured dendritic cells (DC), resulting in a reduction in the upregulation of phenotypic costimulatory signal CD40. Furthermore, PI increased secretion of regulatory cytokines Transforming Growth Factor β1 and Interleukin 10 (IL-10) but reduced the secretion of proinflammatory cytokines IL-6 and IL-17. The data suggest that PI reduces immunogenicity of FVIII by modulating DC maturation and inducing secretion of regulatory cytokines., (Copyright © 2011 Wiley-Liss, Inc.)
- Published
- 2012
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