The Immune Response to Factor Vlll

对因子 VIII 的免疫反应

• 批准号: 8391965
• 负责人: John S. Lollar
• 金额: $ 31.54万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391965
• 关键词: A Mouse; Adjuvant; Affinity; Antibodies; Antibody Formation; Antigen Presentation; Antigens; Autoimmune Process; B-Lymphocytes; Binding; Biological; Blood coagulation; CD4 Positive T Lymphocytes; Cellular Immunology; Complement Factor B; Complication; DAG/PE-Binding Domain; Dendritic Cells; Development; Economic Burden; Epitope Mapping; Epitopes; Evaluation; Family suidae; Helper-Inducer T-Lymphocyte; Hemophilia A; Hemorrhage; Homologous Gene; Human; Hybridomas; Immune response; Immune system; Immunodominant Epitopes; Immunology; In Vitro; Infection; Inflammation; Infusion procedures; Instruction; Intravenous infusion procedures; Lead; Maps; Memory; Memory B-Lymphocyte; Methods; Modeling; Molecular; Monoclonal Antibodies; Mus; Pathogenesis; Pathogenicity; Patient Education; Patients; Play; Proteins; Quality of life; Reagent; Resolution; Roentgen Rays; Role; Scanning; Site-Directed Mutagenesis; Specificity; Structure; Surface Immunoglobulins; Testing; Toxin; Variant; alternative treatment; clinically significant; design; immunogenic; immunogenicity; in vivo; inhibitor/antagonist; macrophage; mutant; novel; novel diagnostics; novel therapeutic intervention; prevent; receptor; research study; response; structural biology; theories; von Willebrand Factor

PROJECT SUMMARY (See instructions): Inhibitory antibodies to factor Vlll develop in approximately 30% of patients with severe and moderately severe hemophilia A in response to infusions of factor Vlll. Inhibitor development is associated with a lower quality of life and an increased economic burden. Consequently, inhibitor development cunrently is considered the most significant complication of the management of in hemophilia A. Additionally, factor Vlll 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 Vlll inhibitor development and to test novel diagnostic and therapeutic approaches to the problem. There are four Specific Aims in this project. In Aim 1, novel immunodominant epitopes recognized by anti-factor Vlll 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 Vlll, and functional analysis of anti-factor Vlll antibodies. Additionally, the pathogenicity of anti-factor Vlll antibodies will be evaluated in hemophilia A mice. In Aim 2, mechanisms of antigen presentation during the immune response to factor Vlll in the murine hemophilia A model will be determined. Factor Vlll is an extremely potent immunogen in hemophilia A mice under conditions in which most proteins are not immunogenic. We will test the hypothesis that antigen presentation by dendritic cells and/or macrophages is more efficient in the case of factor Vlll compared with other proteins. Additionally, we will attempt to identify the underlying mechanism for this phenomenon by identifying receptors that are involved in presentation of factor Vlll. The role von Willebrand factor (VWF) plays in the immune response to factor Vlll is controversial. Our experiments will include determination of whether the immune response to factor Vlll depends on its association with VWF. In Aim 3, the immunogenicity of factor Vlll will be decreased by antigen-specific deletion of naive and memory factor B-cells.

项目摘要（请参阅说明）： 对于因子VLLL的输注，大约30％的严重和中度严重的血友病A患者中，对因子VLLL的抑制性抗体会出现。抑制剂的发展与较低的生活质量和经济负担增加有关。因此，抑制剂的发育被认为是血友病A的管理最重要的并发症。 抑制剂可能发生在非生物友中，产生一种称为获得性血友病的自身免疫性疾病。 最近的发展使得有关因子VLLL抑制剂发展的发病机理的越来越集中的问题成为可能，并测试有关该问题的新型诊断和治疗方法。该项目有四个具体目标。在AIM 1中，由鼠血友病中产生的抗因子VLLL抗体识别出的新型免疫主导表现将是一种免疫原性模型 确定和表征。这将使用几种方法来完成，包括域特异性抗体映射，同源物和定向因子VLLL的诱变以及抗因子VLLL抗体的功能分析。另外，将在血友病A小鼠中评估抗因子VLLL抗体的致病性。在AIM 2中，在鼠中对因子VLLL的免疫反应期间的抗原表现机制 血友病将确定模型。因子VLLL是在大多数蛋白质不是免疫原性的条件下，血友病A小鼠中极有效的免疫原。我们将检验以下假设：与其他蛋白质相比，在因子VLLL的情况下，树突状细胞和/或巨噬细胞的抗原表现更有效。此外，我们将尝试通过鉴定与因子VLLL呈现的受体来识别这种现象的潜在机制。 Von Willebrand因子（VWF）在对因子VLLL的免疫反应中的作用是有争议的。我们的实验将包括确定对因子VLLL的免疫反应是否取决于其与VWF的关联。在AIM 3中，因素VLLL的免疫原性将通过天真和记忆因子B细胞的抗原特异性缺失降低。