Regulation of plasminogen activator inhibitor-1 promotes the immune response to factor VIII in murine hemophilia A.

针对因子VIII（FVIII）的抑制性抗体的产生对接受FVIII产品治疗的血友病A患者产生了巨大影响。纤溶酶原激活物-纤溶酶系统不仅与血栓溶解有关，而且与包括炎症在内的多种反应有关。然而，很少有人知道纤溶成分如何协调免疫反应。在这里，我们表明，纤溶酶原激活物抑制剂-1（派-1），一种纤溶系统的调节剂，是血友病A小鼠模型中控制免疫反应的关键参与者。派-1基因缺失可防止FVIII缺陷小鼠在重复加载FVIII后形成抑制物。派-1缺失与骨髓F4/80阳性细胞的主要组织相容性复合体II类表达减少和T细胞增殖减少相关。移植用靶向派-1的短发夹RNA序列转导的小鼠骨髓细胞以及给予合成派-1抑制剂导致FVIII缺陷小鼠中抗FVIII抗体滴度显著降低。这些结果表明，在FVIII暴露前调节派-1可能是预防血友病A患者发生FVIII抑制物的一种新的治疗选择。

The development of inhibitory antibodies against factor VIII(FVIII) is the enormous impact on hemophilia A patients, who are treated with FVIII products. Plasminogen activator-plasmin system is associated with not only thrombolysis but also various reactions including inflammation. However, little is known about how fibrinolytic components coordinate immune response. Here we show that plasminogen activator inhibitor-1(PAI-1), a regulator of fibrinolytic system, is a key player in controlling immune response in a mouse model of hemophilia A. Genetic deletion of PAI-1 prevented FVIII deficient mice from development of inhibitor formation after repeated loading of FVIII. PAI-1 depletion was associated with decreased major histocompatibility complex class II expression by bone marrow F4/80 positive cells and reduced T cell proliferation. Transplantation of mouse bone marrow cells transduced with a short hairpin RNA sequence targeting PAI-1 as well as administration of synthetic PAI-1 inhibitor caused a significant reduction of anti-FVIII antibody titer in FVIII deficient mice. These results suggest that PAI-1 regulation before FVIII exposure may represent a novel therapeutic option for preventing the development of FVIII inhibitors in hemophilia A patients.