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.

项目总结(见说明)： 在大约30%的重度和中度血友病A患者中，对V11因子的输注会产生抑制V11因子的抗体。抑制剂的开发与较低的生活质量和增加的经济负担有关。因此，目前抑制物的开发被认为是血友病A治疗中最重要的并发症。 抑制物可出现在非血友病患者身上，从而产生一种称为获得性血友病A的自身免疫疾病。 最近的发展使人们有可能提出关于因子Vll抑制剂发展的发病机制的越来越集中的问题，并测试针对该问题的新的诊断和治疗方法。这个项目有四个具体目标。在目标1中，在小鼠血友病模型中产生的抗因子V11抗体识别的新的免疫优势表位将是免疫原性 确定和表征的。这将使用几种方法来完成，包括区域特异性抗体作图，因子V11的同源和定点突变，以及抗因子V11抗体的功能分析。此外，还将评估抗因子V11抗体在血友病A小鼠中的致病性。在目标2中，小鼠对因子V11免疫反应中的抗原提呈机制 血友病A模型将被确定。在血友病A小鼠中，V11因子是一种非常有效的免疫原，在大多数蛋白质不具有免疫原性的条件下。我们将检验这一假设，即在因子V11的情况下，树突状细胞和/或巨噬细胞的抗原提呈比其他蛋白质更有效。此外，我们将试图通过识别参与因子V11呈递的受体来确定这种现象的潜在机制。血管性血友病因子(VWF)在V11因子免疫应答中的作用尚存争议。我们的实验将包括确定对V11因子的免疫反应是否取决于它与VWF的关联。在目标3中，通过抗原特异性删除初始因子和记忆因子B细胞，将降低因子V11的免疫原性。