Downregulation of CD40 signal and induction of TGF-ß by phosphatidylinositol mediates reduction in immunogenicity against recombinant human Factor VIII.
J Pharm Sci
; 101(1): 48-55, 2012 Jan.
Article
em En
| MEDLINE
| ID: mdl-21953409
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 ß1 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fosfatidilinositóis
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Células Dendríticas
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Fator VIII
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Antígenos CD40
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Fator de Crescimento Transformador beta1
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Pharm Sci
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Estados Unidos