Molecular and cellular mechanisms of the FVIII immune response

总体计划-摘要 注射因子(FVIII)抑制性抗体的形成仍然是最具挑战性的问题之一 蛋白替代疗法在甲型血友病患者中的并发症及其与增加 发病率和死亡率。这个U54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，以解决未回答的机械性问题 与FVIII免疫原性有关的问题。我们的创新科学计划是完美整合的，测试新的 假设并带来新的创新技术和来自广泛背景的研究人员 更好地理解FVIII免疫原性项目1(Arruda/Milone)：功能性 跨物种FVIII体液反应的谱系和个体发育。利用免疫蛋白质组学和 基因组学，以帮助严格确定HA患者中抑制物产生细胞的个体发育。他们会 确定对这些患者和HA纵向研究中的抑制物负责的B细胞谱系 使用抑制剂的狗。此外，将定义B细胞生存细胞因子在以下背景下的新角色 FVIII抑制剂。项目2(Herzog)：因子VIII免疫反应的体内机制。利用 创新策略，包括体内可视化技术，以确定哪些抗原提呈细胞(APC) 是MHC II递呈给CD4+T细胞所必需的，这些APC如何与启动FVIII特异性的CD4+T细胞相互作用 细胞，哪些亚群的CD4+T细胞被诱导来促进B细胞的激活，以及天然免疫信号是如何 而微生物群可能会改变这些事件。项目3(Lillicrap)：宿主微生物群对 FVIII免疫原性的机制。创新的初步观察将肠道的元素联系在一起 微生物组在确定FVIII特异性免疫反应中的作用。利用动物研究来研究 宿主肠道微生物群对FVIII免疫反应的调节作用。这条新的调查路线是 提出揭示环境因素与抑制性发展中的变异性之间的关键联系 抗FVIII抗体。项目4(Camire/Krishnaswamy)：第八因子免疫原性--生物学和结构。 这个项目的中心是与FVIII的生物生命周期相关的各种分子物种在 调节免疫反应和抑制物的发展。利用生化和结构生物学 将重点放在驱动免疫反应的FVIII的特性上。一个有待研究的重大假说 该项目涉及FVIII和vWF之间的相互作用所起的调节作用 抑制剂的形成。这一综合提案中包含的多管齐下的方法源自 确定参与调查人员的专业领域，并提供全面调查 探讨FVIII免疫原性的多种生物学机制。

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.