Dasgupta Suryasarathi, Repessé Yohann, Bayry Jagadeesh, Navarrete Ana-Maria, Wootla Bharath, Delignat Sandrine, Irinopoulou Theano, Kamaté Caroline, Saint-Remy Jean-Marie, Jacquemin Marc, Lenting Peter J, Borel-Derlon Annie, Kaveri Srinivas V, Lacroix-Desmazes Sébastien
INSERM Unité 681, Paris, France.
Blood. 2007 Jan 15;109(2):610-2. doi: 10.1182/blood-2006-05-022756. Epub 2006 Sep 19.
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.
血管性血友病因子（VWF）是促凝血因子VIII（FVIII）的伴侣分子。其在降低甲型血友病患者治疗性FVIII免疫原性方面的作用已被提及，但缺乏明确的细胞和分子学依据。在此，我们证明VWF可保护FVIII不被人树突状细胞（DCs）内吞，进而不被呈递给FVIII特异性T细胞。VWF的免疫保护作用需要与FVIII进行物理相互作用，因为在阻碍VWF-FVIII复合物形成时，FVIII的内吞作用显著恢复。有趣的是，VWF对DCs呈递抗原肽的能力或CD4+ T细胞的激活能力均无直接抑制作用。因此，我们提出VWF可能通过在免疫效应器激活上游阻止FVIII进入专业抗原呈递细胞，从而降低FVIII的免疫原性。
