Molecular and cellular mechanisms of the FVIII immune response

FVIII 免疫反应的分子和细胞机制

• 批准号: 10406331
• 负责人: Rodney M Camire
• 金额: $ 138.95万
• 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/10406331
• 关键词: Address; Animals; Antibodies; Antibody Formation; Antigen-Presenting Cells; Area; Automobile Driving; B cell repertoire; B-Cell Activation; B-Lymphocytes; Back; Basic Science; Biochemical; Biological; Biology; CD4 Positive T Lymphocytes; Canis familiaris; Caring; Cell Survival; Cells; Clinical; Complication; Development; Elements; Environmental Risk Factor; Event; F8 gene; Factor VIII; Genomics; Goals; Growth; Hemophilia A; Immune response; Immune signaling; International Aspects; Investigation; Life Cycle Stages; Link; Longitudinal Studies; Molecular; Morbidity - disease rate; PF4 Gene; Pathogenicity; Patients; Play; Property; Records; Research; Research Personnel; Role; Severities; Signal Transduction; Structure; T-Cell Activation; Techniques; Testing; Therapeutic Intervention; VWF gene; Visualization; cytokine; design; enzyme replacement therapy; gut microbiome; host microbiome; immunogenicity; in vivo; inhibitor; innate immune sensing; innovation; innovative technologies; insight; interest; microbiome; mortality; novel; novel therapeutic intervention; prevent; programs; response

Overall Program-Abstract The formation of inhibitory antibodies to infused factor VIII (FVIII) remains one of the most challenging complications of protein replacement therapy in hemophilia A (HA) patients and it is associated with increase morbidity and mortality. This U54 application assembles a cross-disciplinary team of investigators with appropriate track records, research interests and synergistic expertise to address unanswered mechanistic questions related to FVIII immunogenicity. Our innovative scientific program is well-integrated, tests new hypotheses and brings novel innovative technologies and investigators from a wide range of background to better understand FVIII immunogenicity Project 1 (Arruda/Milone): Characterization of the functional repertoire and ontogeny of FVIII humoral response across species. Studies using immunoproteomics and genomics to help rigorously determine the ontogeny of the inhibitor producing cells in HA patients. They will define the B cell repertoires responsible for the inhibitors in these patients and in longitudinal studies in HA dogs with inhibitors. Moreover, the will define the emerging role of B cell survival cytokine in the context of FVIII inhibitors. Project 2 (Herzog): In vivo Mechanism of Immune Response to Factor VIII. Utilizing innovative strategies, including in vivo visualization techniques to define which antigen presenting cells (APCs) are required for MHC II presentation to CD4+ T cells how these APCs interact to prime FVIII-specific CD4+ T cells, which subsets of CD4+ T cells are induced to promote B cell activation, and how innate immune signaling and the microbiome may alter these events. Project 3 (Lillicrap): Influence of the host microbiome on the mechanism of FVIII immunogenicity. Innovative preliminary observations linking elements of the gut microbiome in determining the FVIII-specific immune response. Employing animal studies to investigate the modulatory role of the host gut microbiome on the immune response to FVIII. This novel line of investigation is proposed to reveal a critical link between environmental factors and variability in the development of inhibitory antibodies to FVIII. Project 4 (Camire/Krishnaswamy): Factor VIII Immunogenicity-Biology and Structure. This project centers on the role of various molecular species relevant to the biological life cycle of FVIII in regulating the immune response and inhibitor development. Using biochemical and structural biological approaches to focus on the properties of FVIII driving the immune response. A major hypothesis to be pursued under this project relates to the role played by the interaction between FVIII and vWF as a modulator of inhibitor formation. The multi-pronged approach contained in this integrated proposal derives from the established areas of expertise of the participating investigators and provides a comprehensive investigation into the multiple biological mechanisms underlying the immunogenicity of FVIII.

总体方案-摘要 针对输注的因子VIII（FVIII）的抑制性抗体的形成仍然是最具挑战性的研究之一。 A型血友病（HA）患者蛋白质替代治疗的并发症， 发病率和死亡率。这个U 54应用程序集合了一个跨学科的调查团队， 适当的跟踪记录、研究兴趣和协同专业知识，以解决未解决的机械问题 与FVIII免疫原性相关的问题。我们的创新科学计划是良好的整合，测试新的 假设，并带来了新颖的创新技术和调查人员从广泛的背景， 更好地了解FVIII免疫原性项目1（Arruda/Milone）：功能性 不同种属间FVIII体液应答的库和个体发生。使用免疫蛋白质组学和 基因组学，以帮助严格确定个体发育的抑制剂生产细胞在HA患者。他们将 在这些患者和HA的纵向研究中确定负责抑制剂的B细胞库 有抑制剂的狗此外，本研究将明确B细胞存活细胞因子在以下情况下的新作用： FVIII抑制剂。项目2（Herzog）：对因子VIII的免疫应答的体内机制。利用 创新策略，包括体内可视化技术，以确定哪些抗原呈递细胞（APC） 是MHC II呈递给CD 4 + T细胞所必需的，这些APC如何相互作用以引发FVIII特异性CD 4 + T细胞 细胞，诱导哪些CD 4 + T细胞亚群促进B细胞活化，以及先天免疫信号传导如何 而微生物组可能会改变这些事件。项目3（Lillicrap）：宿主微生物组对 FVIII免疫原性机制。创新的初步观察将肠道的元素联系起来 微生物组在确定FVIII特异性免疫应答中的作用。采用动物研究来调查 宿主肠道微生物组对FVIII免疫应答的调节作用。这条新颖的调查路线是 提出揭示了环境因素和抑制性发展的可变性之间的关键联系， FVIII抗体。项目4（Camire/Krishnaswamy）：因子VIII免疫原性-生物学和结构。 该项目的中心是与FVIII生物生命周期相关的各种分子种类在以下方面的作用： 调节免疫应答和抑制剂的产生。利用生物化学和结构生物学 方法集中于驱动免疫应答的FVIII的性质。一个主要的假设是 本项目涉及FVIII和vWF之间的相互作用作为 抑制剂形成这一综合提案中所载的多管齐下的办法源于 确定参与调查人员的专业领域，并提供全面调查 研究FVIII免疫原性的多种生物学机制。

项目成果

Mice possess a more limited natural antihuman factor VIII antibody repertoire than humans that is produced disproportionately by marginal zone B cells.

小鼠拥有比人类更有限的天然抗人因子 VIII 抗体库，这些抗体库不成比例地由边缘区 B 细胞产生。

• DOI: 10.1016/j.jtha.2023.08.033
• 发表时间: 2024
• 期刊: Journal of thrombosis and haemostasis : JTH
• 作者: Cormier,Matthew;Burnett,Erin;Mo,Aomei;Notley,Colleen;Tijet,Nathalie;Christie-Holmes,Natasha;Hough,Christine;Lillicrap,David
• 通讯作者: Lillicrap,David

Factor IX administration in the skin primes inhibitor formation and sensitizes hemophilia B mice to systemic factor IX administration.

• DOI: 10.1016/j.rpth.2023.102248
• 发表时间: 2023-11
• 期刊: RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS
• 影响因子: 4.6
• 作者: Sherman, Alexandra;Bertolini, Thais B.;Arisa, Sreevani;Herzog, Roland W.;Kaczmarek, Radoslaw
• 通讯作者: Kaczmarek, Radoslaw

Why is AAV FVIII gene therapy not approved by the US Food and Drug Administration yet?

• DOI: 10.1182/bloodadvances.2021004760
• 发表时间: 2021-10-26
• 期刊: Blood advances
• 影响因子: 7.5
• 作者: Arruda VR