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Blood, 15 January 2007, Vol. 109, No. 2, pp. 610-612. Prepublished online as a Blood First Edition Paper on September 19, 2006; DOI 10.1182/blood-2006-05-022756.
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY VWF protects FVIII from endocytosis by dendritic cells and subsequent presentation to immune effectors1 Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U) 681, Paris, France; 2 Université Pierre et Marie CurieParis 6, Institut des Cordeliers, Institut Fédératif de Recherche (IFR) 58, and Institut du Fer a Moulin, IFR 83, Paris, France; 3 Université de Caen, Laboratoire d'hématologie Equipe d'Accueil (EA) 3212, Caen, France; 4 INSERM, U536, U706, Paris, France; 5 Laboratory for Thrombosis and Haemostasis, Department of Hematology, University Medical Center, Utrecht, The Netherlands; 6 Center for Molecular and Vascular Biology, University of Leuven, Belgium
Von Willebrand factor (VWF) is a chaperone molecule for procoagulant factor VIII (FVIII). Its role in the reduction of the immunogenicity of therapeutic FVIII in patients with hemophilia A has been evoked but lacks clear cellular and molecular rationale. Here, we demonstrate that VWF protects FVIII from being endocytosed by human dendritic cells (DCs) and subsequently presented to FVIII-specific T cells. The immunoprotective effect of VWF requires a physical interaction with FVIII because the endocytosis of FVIII was significantly restored on hindering the formation of the VWF-FVIII complex. Interestingly, VWF had no direct inhibitory effect either on the ability of DCs to present antigenic peptides or on the activation potency of CD4+ T cells. We thus propose that VWF may reduce the immunogenicity of FVIII by preventing, upstream from the activation of immune effectors, the entry of FVIII in professional antigen-presenting cells.
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