Downregulation of CD40 signal and induction of TGF-β by phosphatidylinositol mediates reduction in immunogenicity against recombinant human Factor VIII
✍ Scribed by Puneet Gaitonde; Aaron Peng; Robert M. Straubinger; Richard B. Bankert; Sathy V. Balu-iyer
- Publisher
- John Wiley and Sons
- Year
- 2012
- Tongue
- English
- Weight
- 332 KB
- Volume
- 101
- Category
- Article
- ISSN
- 0022-3549
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✦ Synopsis
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 $1 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.