Project-004

项目-004

• 批准号: 10406321
• 负责人: Lei Li
• 金额: $ 25.82万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406321
• 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; innovation; innovative technologies; insight; multidisciplinary; novel; patient subsets; protein expression; protein protein interaction; response; skills; student training; theories; trafficking

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.

治疗血友病A的一个主要障碍是约25%的患者出现高滴度、中和性抗凝血因子VIII抗体。 （FVIII）抗体（抑制剂）。预计这一问题也将 至少在一部分患者中发生于基因治疗后。治疗血友病尤其具有挑战性 产生抑制性抗体的患者。绕过用于治疗这些患者的疗法 有时效力有限且非常昂贵。抗-FVIII抑制性抗体形成是由于 涉及遗传和环境风险因素的复杂多方面免疫反应。几个“危 信号”已被证明与抑制剂形成的风险有关。然而， 激活抗凝血因子VIII反应的触发因素尚未完全了解。例如，具有相同突变的患者 在蛋白质替代治疗后，FVIII基因在抑制剂形成方面可能具有不同的风险。此外，委员会认为， 有一些暗示，不同的FVIII产品可能表现出不同程度的抑制剂风险。近几 多年来，人们已经证明聚糖对免疫系统至关重要，因为其中一些最重要的 免疫系统与病毒或细菌或外源添加的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。糖基化几乎涉及免疫激活途径的每一步。 糖是识别非自身事件的关键，改变的糖组可导致免疫激活， 应答糖基化也参与控制TCR活化阈值的细胞机制， 免疫细胞运输、TCR和BCR信号传导、抗体功能等。我们假设 聚糖在诱导免疫应答或对FVIII耐受性中的作用可以是双重的：一是聚糖与FVIII的相互作用， 糖基化FVIII抗原和具有特异性聚糖谱的宿主免疫系统之间的相互作用可能在 确定诱导抗FVIII免疫应答的风险;第二个是识别并随后 通过外源添加蛋白质或基因表达的免疫激活可以不同程度地改变， FVIII糖组的模式。因此，为了更全面地了解潜在糖基化的谱 对于抗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 在具有不同背景的人和小鼠中抗FVIII应答的发展中的聚糖谱。 接下来，我们将表征通过递送具有不同程度或程度的FVIII分子引起的免疫应答。 糖基化的模式，并探讨免疫激活的机制。通过这项研究，我们希望定义 通过糖基化及其相关机制引发特异性免疫，导致预防或消除 FVIII抑制剂。