Molecular Heterogeneity in FVIII Inhibitor Patients

FVIII 抑制剂患者的分子异质性

• 批准号: 8464234
• 负责人: John S. Lollar
• 金额: $ 36.17万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464234
• 关键词: Affect; Antibodies; B-Lymphocytes; Biological; Biological Assay; Blood Plasma Volume; Bypass; C2 Domain; Coagulation Process; Complication; Cross-Sectional Studies; Data; Development; Dose; Enzyme-Linked Immunosorbent Assay; Epitope Mapping; Epitopes; Event; Fibrin; Generations; Genotype; Goals; Hemophilia A; Hemorrhage; Hemostatic Agents; Heterogeneity; Immune Tolerance; In Vitro; Individual; Infusion procedures; Injury; Institutional Review Boards; Kinetics; Knowledge; Lasers; Life; Maps; Measures; Microfluidics; Microspheres; Missense Mutation; Modeling; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Mus; Pathogenicity; Patients; Phenotype; Pilot Projects; Plasma; Protocols documentation; Recombinants; Recovery; Residual state; Risk; Role; Specificity; Staging; Structure; System; Tail; Testing; Thrombin; Treatment Cost; Variant; antibody inhibitor; base; clinical care; improved; in vitro Assay; in vitro testing; in vivo; inhibitor/antagonist; novel; research clinical testing; response

Thirty percent of patients with severe hemophilia treated with factor fVIII (fVlll) develop anti-fVIII antibodies (inhibitors). This is the most significant complication in the management of patients with hemophilia A leading to significant increases In morbidity as well as cost of treatment. Antibodies to fVIII can also develop in patients with previously normal coagulation leading to acquired hemophilia. These antibodies that develop can inhibit the biological activity of fVIII and necessitate the use of bypassing agents for the treatment of bleeding episodes. However, for unknown reasons, some patients display poor hemostatic response to bypass therapy. Thus, improved treatment options are needed, especially for severe or life-threatening bleeding events. Some biological determinants have been identified that increase the risk of inhibitor development. However, little is known about how hemophilia genotype relates to the ultimate epitope spectrum of the B-cell response or how the epitope spectrum affects the response to treatment and immune tolerance. We have recently shown that epitope specificity and inhibitor kinetics within the C2 domain are more important than inhibitor titer in response to fVlll in acquired hemophilia plasma and a murine monoclonal antibody (MAb) system. The central hypothesis of this project is that the inhibitor epitope spectrum of an individual patient can be used to predict the response to infusions of fVIII with or without bypassing agents. We propose to define further the epitopes on fVIII using a large panel of non-overlapping antl-fVIII MAbs in multiple in vitro assays (Aim 1). Given known discrepancies between the different in vitro assays and bleeding phenotype we will study the importance of different epitopes on murine in vivo bleeding phenotypes and fibrin clot structure (Aim 2). In Aim 3, we will adapt our novel ELISA-based epitope mapping protocol to a more robust microsphere-based assay and investigate in a cross-sectional study how polyclonal patient plasma epitope maps correlate with the response to fVIII and bypassing agents in vitro. Ultimately these results could provide a simple clinical test that may predict response to fVIII and bypassing agents in high titer acquired and congenital hemophilia patients.

30%的重度血友病患者接受因子fVIII（fVIII）治疗后产生抗fVIII抗体 （抑制剂）。这是血友病A患者管理中最重要的并发症， 发病率和治疗费用的显著增加。FVIII的抗体也可以在 既往凝血正常导致获得性血友病的患者。这些产生的抗体 可抑制FVIII的生物活性，并需要使用旁路剂来治疗 出血事件。然而，由于未知的原因，一些患者显示出对药物的不良止血反应。 分流治疗因此，需要改进治疗方案，特别是对于严重或危及生命的 出血事件。一些生物决定因素已被确定，增加风险的抑制剂 发展然而，关于血友病基因型与最终表位的关系知之甚少 B细胞应答的表位谱或表位谱如何影响对治疗和免疫应答 宽容我们最近已经表明，C2结构域内的表位特异性和抑制剂动力学， 在获得性血友病血浆和鼠血浆中，比响应于fVIII的抑制剂滴度更重要。 单克隆抗体（MAb）系统。该项目的中心假设是， 个体患者的光谱可用于预测对有或没有输注fVIII的反应 绕过代理。我们建议使用一个大的非重叠表位组进一步定义FVIII上的表位。 在多个体外测定中的抗I-FVIII MAb（目的1）。鉴于不同体外试验之间的已知差异， 我们将研究不同表位对小鼠体内出血的重要性 表型和纤维蛋白凝块结构（目的2）。在目标3中，我们将调整我们新的基于ELISA的表位作图， 一个更强大的基于微球的测定方案，并在一项横断面研究中研究如何 多克隆患者血浆表位图谱与体外对FVIII和旁路剂的应答相关。 最终，这些结果可以提供一个简单的临床测试，可以预测对FVIII和旁路的反应 高滴度获得性和先天性血友病患者中的药物。