Unité Mixte de Recherche S 872, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France.
Haemophilia. 2012 Mar;18(2):248-54. doi: 10.1111/j.1365-2516.2011.02679.x. Epub 2011 Nov 2.
The development of inhibitory anti-factor VIII (FVIII) antibodies in patients with haemophilia A following replacement therapy is associated with several types of risk factors. Among these, the purity of FVIII concentrates, and in particular the presence of von Willebrand factor (VWF), was controversially proposed to influence the immunogenicity of exogenous FVIII. We re-assessed in vivo and in vitro the immuno-protective effect of VWF towards FVIII. The immuno-protective effect of VWF towards FVIII was investigated in vivo, in a model of haemophilia A. We studied the endocytosis of FVIII by murine bone marrow-derived dendritic cells and evaluated the capacity of VWF to block the internalization of FVIII. We characterized the relevance of VWF for the accumulation of FVIII in the marginal zone of the spleen, a secondary lymphoid organ where the immune response to therapeutically administered FVIII initiates. Our results confirm that VWF reduces the immunogenicity of FVIII in FVIII-deficient mice. Paradoxically, VWF is important for the accumulation of FVIII in the marginal zone of the spleen. We propose that VWF exerts at least two non-mutually exclusive immunoprotective roles towards FVIII in haemophilic mice: VWF prevents the endocytosis of FVIII by professional antigen-presenting cells by blocking the interaction of FVIII with as yet unidentified endocytic receptor(s). Hypothetically, VWF, by virtue of increasing the half-life of FVIII in the circulation, may allow an increased contact time with tolerogenic marginal zone B cells in the spleen.
抑制性抗因子 VIII（FVIII）抗体在接受替代治疗的血友病 A 患者中的产生与多种类型的风险因素有关。其中，FVIII 浓缩物的纯度，尤其是血管性血友病因子（VWF）的存在，被争议性地提出影响外源性 FVIII 的免疫原性。我们重新评估了 VWF 对 FVIII 的体内和体外免疫保护作用。我们在血友病 A 模型中体内研究了 VWF 对 FVIII 的免疫保护作用。我们研究了 FVIII 被鼠骨髓来源的树突状细胞内吞的情况，并评估了 VWF 阻断 FVIII 内化的能力。我们还对 VWF 对 FVIII 在脾脏边缘区（次级淋巴器官，其中对治疗性给予的 FVIII 的免疫反应起始）积累的相关性进行了特征描述。我们的结果证实，VWF 降低了 FVIII 在 FVIII 缺乏型小鼠中的免疫原性。矛盾的是，VWF 对 FVIII 在脾脏边缘区的积累很重要。我们提出，VWF 在血友病小鼠中对 FVIII 至少发挥了两个非相互排斥的免疫保护作用：VWF 通过阻止 FVIII 与尚未鉴定的内吞受体的相互作用，防止 FVIII 被专业抗原呈递细胞内吞。假设性地，VWF 通过增加 FVIII 在循环中的半衰期，可能允许与脾脏中耐受性边缘区 B 细胞增加接触时间。
