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: 10162327
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10162327
• 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/antagonist; intravenous administration; male; microbial; microbiome; microbiota; mouse model; mutant; programs; prophylactic; secondary lymphoid organ; success; trafficking

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 抽象的 大约30％的严重血友病患者对因子VIII（FVIII）的免疫增强响应的发展 A（HA）代表治疗这种情况的最重要的并发症。抗FVIII的形成 抗体（抑制剂）显着损害了这些患者的临床护理及其随后的 管理是不可预测的，实际上挑战，而且通常成本高昂。 FVIII抑制剂的发病机理被认为是复杂且多因素的。大多数发展的患者 这种并发症会在前25次接触FVIII替代疗法中，在前2-3次 生活年。虽然有明显的遗传诱发因素用于抑制剂的发展，例如 突变的F8基因型，一系列获得的影响也有助于抑制剂风险。在这个项目中，我们将 调查迄今为止尚未在这种情况下研究的环境因素的作用 - 肠道 微生物组。有实质性证据表明，肠道微生物组在 系统性免疫系统的开发和调节，并且存在明确的关联 在肠道菌群和某些形式的免疫病理学之间。另外，微生物组 在生命的头两年中，发生了重大变化，最初的FVIII治疗发生了 在患有严重HA的男孩，以及FVIII抑制剂产生的最大风险时期。在项目3中 研究计划我们将解决与微生物组影响FVIII抑制剂有关的三个目标 形成。我们将首先评估变化对肠道微生物组相关的代谢产物的影响 FVIII免疫原性的环境。特别是，我们将确定是否 色氨酸代谢和短链脂肪酸的水平，乙酸，丁酸酯和丙酸 影响先天和适应性免疫调查，以静脉内给予FVIII。在第二个 一系列实验，我们将利用最近开发的无菌HA小鼠进行研究 模型。在这些研究中，我们将从评估FVIII抑制剂开发的可能性开始 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了 通过各种策略进行肠道微生物群，包括来自和没有的HA小鼠的粪便移植 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调节中的作用 对口服输送的FVIII的免疫反应。这些实验将评估FVIII与 各种抗原呈现细胞群体，并将确定FVIII的细胞因子和T细胞环境 肠道相关的淋巴组织，肝脏和脾脏中的免疫反应。总的来说，我们建议 研究计划将提供有关肠道微生物组和 FVIII免疫原性。这些新信息很可能具有巨大的生物学和潜力 翻译含义。