BACKGROUND: The development of factor VIII (FVIII) inhibitors remains the major hurdle in the clinical management of patients with hemophilia A. FVIII uptake by professional antigen-presenting cells (APC) is the first step involved in initiation of immune responses to FVIII. Studies on FVIII catabolism have highlighted the role played by CD91/LRP as a potential target for increasing FVIII half-life in patients and prolonging treatment efficiency. We investigated the involvement of CD91 in FVIII endocytosis by human dendritic cells (DC), a model of professional APC. DESIGN AND METHODS: Immature DC were generated from circulating monocytes from healthy donors. Surface expression of CD91 was assessed by flow cytometry. Uptake of fluorescein isothiocyanate-conjugated ligands by immature DC was studied in the presence of various blocking agents. RESULTS: CD91 was expressed on approximately 20% of DC and mediated the internalization of its model ligand, alpha2-macroglobulin. DC internalized FVIII and activated a human FVIII-specific T-cell clone in a dose-dependent manner. FVIII uptake by DC and subsequent T-cell activation were not inhibited by receptor-associated protein. CONCLUSIONS: Our results indicate that CD91 and other members of the LDL receptor family are not strongly implicated in FVIII internalization by monocyte-derived DC, and suggest the involvement of alternative divalent ion-dependent endocytic receptors.
BACKGROUND: The development of factor VIII (FVIII) inhibitors remains the major hurdle in the clinical management of patients with hemophilia A. FVIII uptake by professional antigen-presenting cells (APC) is the first step involved in initiation of immune responses to FVIII. Studies on FVIII catabolism have highlighted the role played by CD91/LRP as a potential target for increasing FVIII half-life in patients and prolonging treatment efficiency. We investigated the involvement of CD91 in FVIII endocytosis by human dendritic cells (DC), a model of professional APC. DESIGN AND METHODS: Immature DC were generated from circulating monocytes from healthy donors. Surface expression of CD91 was assessed by flow cytometry. Uptake of fluorescein isothiocyanate-conjugated ligands by immature DC was studied in the presence of various blocking agents. RESULTS:CD91 was expressed on approximately 20% of DC and mediated the internalization of its model ligand, alpha2-macroglobulin. DC internalized FVIII and activated a humanFVIII-specific T-cell clone in a dose-dependent manner. FVIII uptake by DC and subsequent T-cell activation were not inhibited by receptor-associated protein. CONCLUSIONS: Our results indicate that CD91 and other members of the LDL receptor family are not strongly implicated in FVIII internalization by monocyte-derived DC, and suggest the involvement of alternative divalent ion-dependent endocytic receptors.
Authors: Puneet Gaitonde; Aaron Peng; Robert M Straubinger; Richard B Bankert; Sathy V Balu-Iyer Journal: J Pharm Sci Date: 2011-09-23 Impact factor: 3.534
Authors: Y Dargaud; A Pavlova; S Lacroix-Desmazes; K Fischer; M Soucie; S Claeyssens; D W Scott; R d'Oiron; G Lavigne-Lissalde; G Kenet; C Escuriola Ettingshausen; A Borel-Derlon; T Lambert; G Pasta; C Négrier Journal: Haemophilia Date: 2016-01 Impact factor: 4.287
Authors: Aleksandra Wroblewska; Simon D van Haren; Eszter Herczenik; Paul Kaijen; Aleksandra Ruminska; Sheng-Yu Jin; X Long Zheng; Maartje van den Biggelaar; Anja ten Brinke; Alexander B Meijer; Jan Voorberg Journal: Blood Date: 2012-04-12 Impact factor: 22.113