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 A 型血友病的一个主要障碍是约 25% 的患者会产生高滴度的中和性抗因子 VIII (FVIII) 蛋白质替代疗法后的抗体（抑制剂）。预计这个问题也会 至少一部分患者在基因治疗后发生。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 有时效果有限且成本高昂。抗 FVIII 抑制性抗体的形成源自 复杂的多方面免疫反应，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相关。然而，潜在的 激活抗 FVIII 反应的触发因素尚不完全清楚。例如，具有相同突变的患者 FVIII 基因中的 FVIII 基因在蛋白质替代疗法后的抑制剂开发中可能具有不同的风险。而且， 这表明不同的 FVIII 产品可能表现出不同程度的抑制剂风险。近来 多年来，已经证明聚糖对于免疫系统至关重要，因为一些最重要的聚糖 介导免疫系统与病毒或细菌或外源添加蛋白质之间的相互作用 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一步。 聚糖是识别非自身事件的关键，糖组的改变可以导致免疫系统的激活 回应。糖基化还参与控制 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 聚糖在诱导 FVIII 免疫反应或耐受中的作用可以有两个方面：一是相互作用 糖基化 FVIII 抗原和具有特定聚糖谱的宿主免疫系统的相互作用在以下方面可能具有重要意义： 确定诱导抗 FVIII 免疫反应的风险；第二是承认并随之而来 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或改变 FVIII 糖组的模式。因此，为了更全面地了解潜在的糖基化谱 抗 FVIII 抑制剂反应发展的影响，我们建议首先研究宿主的影响 不同背景的人类和小鼠抗 FVIII 反应发展中的聚糖谱。 接下来，我们将表征通过不同程度或不同程度的 FVIII 分子递送引起的免疫反应。 糖基化模式并研究免疫激活机制。通过这项研究，我们希望定义 糖基化及其相关机制引起的特异性免疫触发，导致预防或消除 FVIII 抑制剂。