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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.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Brief report
VWF protects FVIII from endocytosis by dendritic cells and subsequent presentation to immune effectors
Suryasarathi Dasgupta1,2,
Yohann Repessé1,3,
Jagadeesh Bayry1,2,
Ana-Maria Navarrete1,2,
Bharath Wootla1,2,
Sandrine Delignat1,2,
Theano Irinopoulou2,4,
Caroline Kamaté5,
Jean-Marie Saint-Remy6,
Marc Jacquemin6,
Peter J. Lenting5,
Annie Borel-Derlon3,
Srinivas V. Kaveri1,2, and
Sébastien Lacroix-Desmazes1,2,
1 Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U) 681, Paris, France;
2 Université Pierre et Marie Curie–Paris 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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