Center for the Investigation of Factor VIII Inhibitors and Glycosylation

因子 VIII 抑制剂和糖基化研究中心

• 批准号: 10227911
• 负责人: Lei Li
• 金额: $ 134.67万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 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/10227911
• 关键词: Antibodies; Antibody Formation; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Bacteria; Binding; Blood coagulation; Bypass; Caring; Cells; Clinical Treatment; Complex; Complication; Data Analyses; Development; Engineering; Environment; Environmental Risk Factor; Epitopes; Event; Exhibits; F8 gene; Face; Factor VIII; Frequencies; Gene Expression; Genes; Genetic; Genetic Risk; Glycobiology; Glycopeptides; Glycoproteins; Hemophilia A; Hemorrhage; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunologics; Immunology; Infrastructure; Investigation; Lateral; Lead; Mass Spectrum Analysis; Mediating; Microarray Analysis; Morbidity - disease rate; Mouse Strains; Mus; Mutation; Oligosaccharides; Organ; Pathway interactions; Patients; Pattern; Peptide Hydrolases; Physicians; Polysaccharides; Prevention; Protein Glycosylation; Proteins; Quality of life; Regimen; Replacement Therapy; Research; Research Personnel; Research Project Grants; Risk; Role; Services; Severities; Signal Transduction; Specificity; Surveys; T-Lymphocyte; TCR Activation; Technology; Tissues; Training; Training and Education; Variant; Virus; adaptive immune response; antibody inhibitor; base; cell growth regulation; cost; enzyme replacement therapy; gene therapy; glycoproteomics; glycosylation; immune activation; immunoregulation; inhibitor/antagonist; innovation; innovative technologies; insight; multidisciplinary; novel; patient subsets; protein expression; protein protein interaction; response; skills; student training; theories; trafficking; Antibodies; Antibody Formation; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Bacteria; Binding; Blood coagulation; Bypass; Caring; Cells; Clinical Treatment; Complex; Complication; Data Analyses; Development; Engineering; Environment; Environmental Risk Factor; Epitopes; Event; Exhibits; F8 gene; Face; Factor VIII; Frequencies; Gene Expression; Genes; Genetic; Genetic Risk; Glycobiology; Glycopeptides; Glycoproteins; Hemophilia A; Hemorrhage; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunologics; Immunology; Infrastructure; Investigation; Lateral; Lead; Mass Spectrum Analysis; Mediating; Microarray Analysis; Morbidity - disease rate; Mouse Strains; Mus; Mutation; Oligosaccharides; Organ; Pathway interactions; Patients; Pattern; Peptide Hydrolases; Physicians; Polysaccharides; Prevention; Protein Glycosylation; Proteins; Quality of life; Regimen; Replacement Therapy; Research; Research Personnel; Research Project Grants; Risk; Role; Services; Severities; Signal Transduction; Specificity; Surveys; T-Lymphocyte; TCR Activation; Technology; Tissues; Training; Training and Education; Variant; Virus; adaptive immune response; antibody inhibitor; base; cell growth regulation; cost; enzyme replacement therapy; gene therapy; glycoproteomics; glycosylation; immune activation; immunoregulation; inhibitor/antagonist; innovation; innovative technologies; insight; multidisciplinary; novel; patient subsets; protein expression; protein protein interaction; response; skills; student training; theories; trafficking

PROJECT SUMMARY A major obstacle in treating hemophilia A is that ~25% of patients develop high-titer, neutralizing anti-factor VIII (FVIII) antibodies (inhibitors) following protein replacement therapy. It is also anticipated that this problem will occur following gene therapy in at least a subset of patients. It is particularly challenging to treat hemophilia patients who have developed inhibitory antibodies. Bypassing therapies that are used to treat these patients sometimes have limited efficacy and are very costly. The anti-FVIII inhibitory antibody formation results from a complex multifaceted immune response involving both genetic and environmental risk factors. Several “danger signals” have been demonstrated to be associated with risks of inhibitor formation. However, the potential triggers to activate anti-FVIII responses are not fully understood. For example, patients with identical mutations in FVIII gene can have differential risks in inhibitor development following protein replacement therapy. Moreover, there were some implications that different FVIII products may exhibit different degrees of inhibitor risks. In recent years, it has been demonstrated that glycans are crucial for the immune system, as some of the most important interactions between the immune system and viruses or bacteria or exogenously added proteins are mediated by protein-glycan interactions. Glycosylation is involved in almost every step of the immune activation pathway. Glycans are a key in the recognition of non-self events and an altered glycome can lead to activation of immune responses. Glycosylation is also involved in the cellular mechanisms that control the threshold of TCR activation, immune cell trafficking, TCR and BCR signaling, antibody function, and more. We hypothesize that the impact of glycans in the induction of immune response or tolerance to FVIII can be two-fold: one is that the interaction of glycosylated FVIII antigens and host immune system with specific glycan profiles can be significant in determining the risk of inducing anti-FVIII immune response; and the second is that the recognition of and ensued immune activation by exogenously added protein or gene expression can be altered by different extent or patterns of FVIII glycomes. Therefore, in order to more fully understand the spectrum of potential glycosylation influence on the development of anti-FVIII inhibitor responses, we propose to first look into the influence of host glycan profiles in the development of anti-FVIII response both in humans and mice with different backgrounds. Next we will characterize the immune responses elicited by delivery of FVIII molecules with different extent or patterns of glycosylation and investigate the mechanism of immune activation. From this study, we wish to define specific immunologic trigger by glycosylation and its associated mechanisms, leading to prevention or elimination of FVIII inhibitors.

项目摘要 治疗血友病A的主要障碍是约有25％的患者患有高素质，中和抗因子VIII （FVIII）蛋白质替代疗法后的抗体（抑制剂）。还可以预料到这个问题 至少在一部分患者中发生基因治疗。治疗血友病特别具有挑战性 患有抑制性抗体的患者。绕过用于治疗这些患者的疗法 有时效率有限，而且成本很高。抗FVIII抑制性抗体的形成是由A产生的 复杂的多方面免疫响应涉及遗传和环境风险因素。几个“危险” 信号已被证明与抑制剂形成的风险有关。但是，潜力 尚不完全了解激活抗FVIII反应的触发因素。例如，突变相同的患者 在FVIII中，基因在蛋白质替代治疗后抑制剂发育中可能会有差异风险。而且， 有一些影响是不同程度的抑制剂风险可能存在不同程度的FVIII产品。最近 多年来，已经证明，聚糖对于免疫系统至关重要，因为一些最重要的 免疫系统与病毒或细菌或外源蛋白质之间的相互作用是介导的 通过蛋白质 - 聚糖相互作用。糖基化几乎参与免疫激活途径的每个步骤。 聚糖是识别非自我事件的关键，而变化的Glyce可以导致免疫激活 回答。糖基化也参与控制TCR激活阈值的细胞机制， 免疫细胞运输，TCR和BCR信号传导，抗体功能等。我们假设影响 在诱导免疫反应或对FVIII的耐受性时，聚糖的含量可能是两个方面：一个是相互作用 具有特定聚糖剖面的糖基化FVIII抗原和宿主免疫系统在 确定诱导抗FVIII免疫反应的风险；第二个是认可和确保 通过不同程度或 FVIII Glycos的模式。因此，为了更充分了解潜在糖基化的光谱 对抗FVIII抑制剂反应的发展的影响，我们建议首先研究宿主的影响 在人类和具有不同背景的小鼠抗FVIII反应发展中的聚糖谱。 接下来，我们将通过不同程度或不同程度或 糖基化的模式并研究免疫激活的机制。从这项研究中，我们希望定义 糖基化及其相关机制通过特定的免疫触发触发，导致预防或紧急 FVIII抑制剂。