Characterization of the Functional Repertoire and Ontogeny of FVIII Humoral Response Across Species: Project 1

跨物种 FVIII 体液反应的功能库和个体发育特征：项目 1

• 批准号: 10406333
• 负责人: Valder R. Arruda
• 金额: $ 34.62万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406333
• 关键词: Address; Affinity; Amino Acids; Animal Model; Antibodies; Antibody Repertoire; Antigens; Autoimmune Diseases; B cell repertoire; B-Lymphocytes; Binding; Blood; Canis familiaris; Caring; Cell Survival; Complication; Data; Deuterium; Development; Discipline; Disease; Disease model; Dog Diseases; Epitopes; Evolution; Exposure to; F8 gene; Factor VIII; Genes; Goals; Growth; Hemophilia A; Human; Immune; Immune response; Immune system; Immunologics; Investigation; Knowledge; Laboratories; Liquid Chromatography; Lupus; Maps; Mass Spectrum Analysis; Mediating; Methods; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Pathologic; Patients; Peripheral Blood Mononuclear Cell; Phage Display; Pre-Clinical Model; Process; Prognosis; Proteomics; Recombinants; Relapse; Research Personnel; Resolution; Role; Sampling; Scientist; Series; Specificity; Technology; Testing; Time; Variant; Work; base; canine model; career; clinical translation; cohort; cytokine; human data; immunogenic; immunogenicity; inhibitor; innovation; insight; mortality; next generation; novel; novel therapeutic intervention; novel therapeutics; preclinical development; recruit; response; skill acquisition; tandem mass spectrometry

Project 1 - Abstract The formation of Factor VIII (FVIII) inhibitor is a main complication of the treatment of hemophilia A (HA) and it is associated with increased morbidity and mortality. The overall goal of this project is to gain insights into why FVIII is immunogenic by understanding how FVIII is targeted by the humoral immune system. We hypothesize that the FVIII-specific humoral immune response is composed of a diverse and dynamic antibody repertoire. We assembled a group of investigators from a variety of complementary scientific background that together will overcome major gaps in knowledge on FVIII immunogenicity and B cells. We will employ innovative and state-of-art technologies to broad our current understanding of the underlying mechanism of inhibitor formation to FVIII. We propose the following aims: Aim 1: Define the clonal repertoire and epitope specificity of circulating anti-FVIII antibodies in patients with HA. Taking a novel immunomics approach, we will, for the first time, characterize in detail the FVIII epitopes recognized by FVIII-specific antibodies as well as clonal relationships of the related B cells in HA patients with inhibitors. Aim 2: Define the FVIII antibody repertoire and its dynamics in canine HA inhibitor models. Utilizing antigen phage display for the first time in canine disease models, we will longitudinally characterize the FVIII-driven humoral immune response, which will provide insight into the intrinsic immunogenicity of FVIII. Results from this work will be compared to data from Aim 1 to further validate the HA dog model. Aim 3: Investigate the role of B cell survival cytokines in inhibitor formation, epitope diversity and eradication. Emerging evidence implicates B cell survival cytokines, including BLyS, in immune-mediated diseases. Our preliminary data suggests that BLyS may have a role in FVIII inhibitors. Herein, we will comprehensively evaluate the contribution of BLyS to FVIII immunogenicity through a series of studies in human and murine HA models. Together these studies will provide insights on the humoral immune system in FVIII immunogenicity, including establishing a framework for novel therapeutic approaches and testing the validity of small and large preclinical models.

项目1-摘要 凝血因子VIII(FVIII)抑制物的形成是治疗急性心肌梗死的主要并发症 血友病A(HA)，它与发病率和死亡率增加有关。总目标 这个项目的目的是通过了解FVIII是如何免疫的来深入了解FVIII为什么是免疫原性的 以体液免疫系统为靶标。我们假设FVIII特有的幽默 免疫应答是由一系列多样的动态抗体组成的。我们组装了一个 来自各种互补科学背景的研究人员小组将共同努力 克服在FVIII免疫原性和B细胞方面的主要知识空白。我们将聘用 创新和最先进的技术，以扩大我们目前对潜在的 对FVIII的抑制作用机理。我们提出以下目标：目标1：界定 患者循环中抗FVIII抗体的克隆库和表位特异性 带着HA。采用一种新的免疫组学方法，我们将首次表征 详细说明FVIII特异性抗体识别的FVIII表位以及克隆 甲肝患者相关B细胞与抑制剂的关系目标2：定义FVIII 犬HA抑制剂模型中的抗体库及其动态。利用抗原 首次在犬病模型中展示噬菌体，我们将纵向表征 FVIII驱动的体液免疫反应，这将提供对内在 FVIII的免疫原性。这项工作的结果将与目标1至 进一步验证HA犬模型。目的3：探讨B细胞存活细胞因子的作用 在抑制物的形成、表位多样性和根除方面。新出现的证据表明B组 免疫介导性疾病中的细胞生存细胞因子，包括BLyS。我们的初步数据 提示BLyS可能在FVIII抑制剂中起作用。在这里，我们将全面 通过一系列人体研究评价BLyS对FVIII免疫原性的贡献 和小鼠HA模型。总之，这些研究将为体液免疫提供见解。 FVIII免疫原性系统，包括为新的治疗方法建立框架 方法和检验小型和大型临床前模型的有效性。