Aflac Cancer and Blood Disorders Service, Emory University, Atlanta, Georgia.
Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, Indiana.
Haemophilia. 2019 Jul;25(4):595-602. doi: 10.1111/hae.13740.
Inhibitor formation against coagulation factor VIII (FVIII) is an unresolved serious problem in replacement therapy for the X-linked bleeding disorder haemophilia A. Although FVIII inhibitors have been extensively studied, much of the basic mechanism of this immune response remains to be uncovered.
Within the NHLBI State of the Science Workshop on Factor VIII Inhibitors, Working Group 3 identified three scientific priorities for basic and translational research on FVIII inhibitor formation.
A larger list of potential areas of research was initially developed as a basis for subsequent prioritization. Each scientific goal was further evaluated based on required effort, potential impact, approach, methods, technologies and models.
The three priorities include the following: activation signals and immune regulation that shape the response to FVIII (including innate immunity, microbiome, adaptive immunity and regulatory T cell studies in humans); utility of animal models and non-animal approaches (in silico, genetic, single-cell/sorted population "omics," in vitro) to help predict inhibitor formation and identify novel therapeutics; and impact of the source of FVIII, its structure and von Willebrand factor on immunogenicity and tolerance.
Early interactions between FVIII and the immune system, biomarker development and studies in different patient groups (previously treated or untreated, with or without inhibitor formation, patients undergoing immune tolerance induction or gene therapy) deserve particular emphasis. Finally, linking basic to clinical studies, development of a repository for biospecimens and opportunities for interdisciplinary research training are important components to solving the urgent problem of inhibitor formation.
在针对凝血因子 VIII（FVIII）的替代疗法中，抑制物的形成是一个尚未解决的严重问题，这种替代疗法用于治疗 X 连锁出血性疾病血友病 A。尽管已经对 FVIII 抑制剂进行了广泛的研究，但这种免疫反应的许多基本机制仍有待发现。
在 NHLBI 关于 FVIII 抑制剂的科学现状研讨会上，第 3 工作组确定了针对 FVIII 抑制剂形成的基础和转化研究的三个科学优先事项。
最初开发了一个潜在研究领域的更大列表，作为随后进行优先排序的基础。根据所需的努力、潜在影响、方法、方法、技术和模型，进一步评估了每个科学目标。
三个优先事项包括以下内容：影响 FVIII （包括先天免疫、微生物组、适应性免疫和人类调节性 T 细胞研究）反应的激活信号和免疫调节；动物模型和非动物方法（计算、遗传、单细胞/分类群体“组学”、体外）的应用，以帮助预测抑制剂的形成并确定新的治疗方法；FVIII 的来源、其结构和血管性血友病因子对免疫原性和耐受性的影响。
FVIII 与免疫系统之间的早期相互作用、生物标志物的发展以及不同患者群体（以前接受过治疗或未接受过治疗、有或没有抑制剂形成、正在接受免疫耐受诱导或基因治疗的患者）的研究应特别强调。最后，将基础研究与临床研究联系起来、建立生物标本库以及为跨学科研究培训提供机会是解决抑制剂形成这一紧迫问题的重要组成部分。
