Project-005

项目-005

基本信息

批准号：
10227919
负责人：
Lei Li
金额：
$ 27.49万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
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/10227919
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

项目摘要

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）预计这个问题也会出现。至少有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。已产生抑制性抗体的患者，绕过用于治疗这些患者的疗法。抗 FVIII 抑制性抗体的形成有时效果有限且成本非常高。复杂的多方面免疫反应，涉及遗传和环境风险因素。信号”已被证明与抑制剂形成的风险相关。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 基因中的蛋白质替代疗法后抑制剂的形成可能具有不同的风险。最近，不同的 FVIII 产品可能表现出不同程度的抑制剂风险。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糖基化也参与控制 TCR 激活阈值的细胞机制，我们捕捉到了免疫细胞运输、TCR 和 BCR 信号传导、抗体功能等的影响。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；第二是识别并随之发生；外源添加的蛋白质或基因表达可以不同程度或不同程度地激活免疫因此，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。我们希望通过这项研究来定义糖基化模式并研究免疫激活机制。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。