Influence of the Host Microbiome on the Mechanism of FVIII Immunogenicity: Project 3

宿主微生物组对 FVIII 免疫原性机制的影响：项目 3

• 批准号: 10406335
• 负责人: DAVID P LILLICRAP
• 金额: $ 18.6万
• 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/10406335
• 关键词: Acetates; Address; Age; Animals; Antibiotic Therapy; Antibiotics; Antibodies; Antigen-Presenting Cells; Area; Biological; Blood Coagulation Disorders; Butyrates; Bypass; Cell Communication; Complex; Complication; Development; Diet; Disease; Environment; Environmental Risk Factor; Evaluation; Evolution; Exposure to; F8 gene; Factor VIII; Generations; Genetic; Genetic Engineering; Genotype; Germ-Free; Gut associated lymphoid tissue; Hemophilia A; Hemostatic Agents; Human; Image; Immune; Immune Tolerance; Immune response; Immune system; Incidence; Infusion procedures; Inherited; Intervention; Intravenous; Investigation; Isoantibodies; Knowledge; Label; Life; Liver; Location; Mediating; Modification; Molecular; Mucous Membrane; Mus; Mutation; Natural Immunity; Nutrient; Oral; Outcome; Pathogenesis; Patient Care; Patients; Persons; Pharmaceutical Preparations; Plasma; Play; Population; Predisposing Factor; Propionates; Protocols documentation; Recurrence; Regimen; Regulation; Replacement Therapy; Research; Risk; Role; Secondary to; Series; Spleen; Surface; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Tryptophan Metabolism Pathway; Volatile Fatty Acids; adaptive immune response; adaptive immunity; antibody inhibitor; boys; clinical care; cofactor; cost; cytokine; dietary; dysbiosis; experimental study; fecal transplantation; gut microbes; gut microbiome; gut microbiota; host microbiome; immunogenicity; immunopathology; infancy; inhibitor; intravenous administration; male; microbial; microbiome; microbiota; mouse model; mutant; programs; prophylactic; secondary lymphoid organ; success; trafficking; translational potential

Project 3 Abstract The development of an immune response to factor VIII (FVIII) in ~30% of persons with severe hemophilia A (HA) represents the most important complication of treating this condition. The formation of anti-FVIII antibodies (inhibitors) significantly compromises the clinical care of these patients, and their subsequent management is less predictable, practically challenging and often extraordinarily costly. The pathogenesis of FVIII inhibitors is recognized to be complex and multifactorial. Most patients that develop this complication do so during the first 25 exposures to FVIII replacement therapy, within the first 2-3 years of life. While there are clear genetic predisposing factors for inhibitor development, such as the mutant F8 genotype, a range of acquired influences also contribute to inhibitor risk. In this project, we will investigate the role of an environmental factor that, to date, has not been studied in this context – the gut microbiome. There is substantive evidence that the gut microbiome plays an important role in the development and regulation of the systemic immune system, and that there are clear associations between the gut microbiota and certain forms of immunopathology. In addition, the microbiome undergoes significant changes during the first two years of life, the time when initial FVIII treatment occurs in boys with severe HA, and the period of maximum risk for FVIII inhibitor generation. In Project 3 of this research program we will address three objectives related to microbiome influences on FVIII inhibitor formation. We will first evaluate the influence of changes to the gut microbiome-related metabolite environment on the immunogenicity of FVIII. In particular, we will determine whether the products of tryptophan metabolism and levels of the short chain fatty acids, acetate, butyrate and propionate influence innate and adaptive immune responses to intravenously administered FVIII. In the second series of experiments, we will conduct studies utilizing our recently developed germ-free HA mouse model. In these studies, we will begin with an assessment of the likelihood for FVIII inhibitor development in the absence of gut microbes, and will then progress to studies in which we selectively repopulate the gut microbiota through various strategies including fecal transplantation from HA mice with and without FVIII inhibitors. Lastly, we will conduct studies to evaluate the role of the gut microbiome in regulating the immune response to orally delivered FVIII. These experiments will assess the interaction of FVIII with various antigen presenting cell populations and will determine the cytokine and T cell context of the FVIII immune response in the gut associated lymphoid tissue, liver and spleen. Overall, we propose that this program of research will provide important new knowledge concerning the role of the gut microbiome and FVIII immunogenicity. This new information is very likely to have significant biological and potential translational implications.

项目 3 摘要 在约30%的重度血友病患者中发生对凝血因子VIII（FVIII）的免疫应答 A（HA）是治疗这种疾病最重要的并发症。抗FVIII抗体的形成 抗体（抑制剂）显著损害了这些患者的临床护理， 管理的可预测性较低，在实践中具有挑战性，而且往往费用高昂。的 FVIII抑制剂的发病机制被认为是复杂和多因素的。大多数患者 这种并发症在前25次暴露于FVIII替代治疗期间发生，在前2-3次暴露期间发生， 多年的生活。虽然有明显的遗传易感因素抑制剂的发展，如 突变的F8基因型，一系列获得性影响也有助于抑制剂的风险。在这个项目中，我们将 调查一个环境因素的作用，迄今为止，还没有在这种情况下研究-肠道 微生物组有实质性证据表明，肠道微生物组在消化道疾病中起着重要作用。 发展和调节系统免疫系统，并有明确的关联 肠道菌群和某些形式的免疫病理学之间的联系。此外，微生物群 在出生后的头两年（即首次FVIII治疗时）发生显著变化 在重度HA男孩中，以及FVIII抑制物生成的最大风险期。在项目3中， 研究计划，我们将解决与微生物群对FVIII抑制剂影响相关的三个目标 阵我们将首先评估肠道微生物组相关代谢物变化的影响 环境对FVIII免疫原性的影响。特别是，我们将确定产品是否 色氨酸代谢和短链脂肪酸、乙酸、丁酸和丙酸的水平 影响对静脉内施用的FVIII的先天性和适应性免疫应答。在第二 在一系列实验中，我们将利用我们最近开发的无菌HA小鼠进行研究 模型在这些研究中，我们将开始评估FVIII抑制物形成的可能性 在没有肠道微生物的情况下，然后将进行研究，我们选择性地重新填充 肠道微生物群通过各种策略，包括粪便移植从HA小鼠与和没有 FVIII抑制剂。最后，我们将进行研究，以评估肠道微生物组在调节 口服FVIII的免疫应答。这些实验将评估FVIII与 各种抗原呈递细胞群，并将决定FVIII的细胞因子和T细胞背景 肠道相关淋巴组织、肝脏和脾脏中的免疫应答。总的来说，我们建议， 研究计划将提供有关肠道微生物组作用的重要新知识， FVIII免疫原性。这一新的信息很可能具有重大的生物学意义和潜力 翻译的含义。