The Immune Response to Factor VIII

约30%的重度和中重度血友病A患者在接受因子VIII输注后产生因子VIII抑制性抗体。抑制物的产生与较低的生活质量和增加的经济负担有关。因此，目前认为抑制物形成是血友病A治疗中最重要的并发症。此外，因子VIII抑制剂可发生在非血友病患者中，产生称为获得性血友病A的自身免疫性疾病。最近的事态发展使人们有可能问越来越集中的问题，因子VIII抑制剂的发展的发病机制，并测试新的诊断和治疗方法的问题。这个项目有两个具体目标。在目的1中，将鉴定和表征在鼠血友病A免疫原性模型中产生的抗因子VIII抗体识别的新型免疫显性表位。这将使用几种方法来实现，包括结构域特异性抗体作图、因子VIII的同源物和定点诱变以及抗因子VIII抗体的功能分析。此外，将在血友病A小鼠中评价抗因子VIII抗体的致病性。在目标2中，目标1中产生的具有确定特异性的鼠抗体将用于鉴定人血友病A患者识别的新型因子VIII抗体表位。

Inhibitory antibodies to factor VIII develop in approximately 30% of patients with severe and moderately severe hemophilia A in response to infusions of factor VIII. Inhibitor development is associated with a lower quality of life and an increased economic burden. Consequently, inhibitor development currently is considered the most significant complication of the management of in hemophilia A. Additionally, factor VIII inhibitors can occur in nonhemophiliacs, producing an autoimmune condition called acquired hemophilia A. Recent developments have made it possible to ask increasingly focused questions regarding the pathogenesis of factor VIII inhibitor development and to test novel diagnostic and therapeutic approaches to the problem. There are two Specific Aims in this project. In Aim 1, novel immunodominant epitopes recognized by anti-factor VIII antibodies produced in a murine hemophilia A immunogenicity model will be identified and characterized. This will be accomplished using several methods, including domain-specific antibody mapping, homolog and site-directed mutagenesis of factor VIII, and functional analysis of anti-factor VIII antibodies. Additionally, the pathogenicity of anti-factor VIII antibodies will be evaluated in hemophilia A mice. In Aim 2, murine antibodies of defined specificity produced in Aim 1 will be used to identify novel factor VIII antibody epitopes recognized by human hemophilia A patients.