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Downregulation of CD40 signal and induction of TGF-β by phosphatidylinositol mediates reduction in immunogenicity against recombinant human Factor VIII.
- Source :
-
Journal of Pharmaceutical Sciences . Jan2012, Vol. 101 Issue 1, p48-55. 8p. - Publication Year :
- 2012
-
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. © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:48-55, 2012 [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00223549
- Volume :
- 101
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Journal of Pharmaceutical Sciences
- Publication Type :
- Academic Journal
- Accession number :
- 67365987
- Full Text :
- https://doi.org/10.1002/jps.22746