Submitted May 11, 2006
Accepted September 4, 2006
VWF protects FVIII from endocytosis by dendritic cells and subsequent presentation to immune effectors
Suryasarathi Dasgupta, Yohann Repesse, Jagadeesh Bayry, Ana-Maria Navarrete, Bharath Wootla, Sandrine Delignat, Theano Irinopoulou, Caroline Kamate, Jean-Marie Saint-Remy, Marc Jacquemin, Peter J Lenting, Annie Borel-Derlon, Srinivas V Kaveri, and Sebastien Lacroix-Desmazes*
INSERM U681, Paris, France
Universite de Caen, Laboratoire d'hematologie, Caen, France
Institut du Fer a Moulin, Paris, France
Laboratory for Thrombosis and Haemostasis, University Medical Center, Utrecht, The Netherlands
Center for Molecular and Vascular Biology, Katolische Universtitat Leuven, Belgium
* Corresponding author; email: sebastien.lacroix-desmazes{at}umrs681.jussieu.fr.
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 rational. 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, as the endocytosis of FVIII was significantly restored upon 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.
