The Immune Response to Factor VIII

大约30%的重度和中度血友病A患者在注射因子VIII后会产生抑制因子VIII的抗体。抑制抗体的产生与较低的生活质量和增加的经济负担有关。因此，抑制物的开发目前被认为是血友病A治疗中最重要的并发症。此外，因子抑制剂可出现在非血友病患者中，产生一种称为获得性血友病A的自身免疫性疾病。最近的发展使人们有可能就因子抑制物开发的发病机制提出越来越集中的问题，并测试针对该问题的新的诊断和治疗方法。这个项目有两个具体目标。在目标1中，将鉴定和表征在小鼠血友病A免疫原性模型中产生的抗第VIII因子抗体识别的新的免疫优势表位。这将使用几种方法来完成，包括区域特异性抗体作图，第八因子的同源和定点突变，以及抗第八因子抗体的功能分析。此外，还将评估抗第VIII因子抗体在血友病A小鼠中的致病性。在目标2中，在目标1中产生的特定特异性的小鼠抗体将用于鉴定人类血友病A患者识别的新的第VIII因子抗体表位。

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.