Project 3: Immune regulation by cellular glycosylation for the inhibitory antibody development to factor VIII in hemophilia

项目 3：通过细胞糖基化进行免疫调节，以抑制血友病中因子 VIII 的抗体发展

• 批准号: 10406319
• 负责人: Carol H Miao
• 金额: $ 48.98万
• 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/10406319
• 关键词: Antibodies; Antibody Formation; Antigens; B-Lymphocytes; Bacteria; Bypass; Cells; Clinical; Complex; Development; Engineering; Environmental Risk Factor; Epitopes; Event; Exhibits; F8 gene; Factor VIII; Gene Expression; Genes; Genetic Risk; Glycopeptides; Hemophilia A; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunologics; Injections; Investigation; Lead; Mediating; Mouse Strains; Mus; Mutation; Pathway interactions; Patients; Pattern; Peptides; Plasma; Plasmids; Polysaccharides; Prevention; Process; Proteins; Rapid screening; Recombinants; Risk; Signal Transduction; Specificity; T cell response; T-Lymphocyte; TCR Activation; Variant; Virus; antibody inhibitor; cell growth regulation; cost; enzyme replacement therapy; gene therapy; glycosylation; immune activation; immunogenic; immunoregulation; inhibitor; mouse model; patient subsets; protein expression; response; trafficking; treatment center

PROJECT 3: 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 twofold: 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3：概要 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。用于治疗这些患者的替代疗法 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-FVIII应答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，有一些暗示，不同的FVIII产物可能表现出不同程度的抑制剂， 风险近年来，已经证明聚糖对于免疫系统是至关重要的，因为其中的一些聚糖在免疫系统中起重要作用。 免疫系统与病毒、细菌或外源性添加物之间最重要的相互作用 蛋白质由蛋白质-聚糖相互作用介导。糖基化几乎参与了蛋白质合成的每一步。 免疫激活途径糖是识别非自我事件和改变的糖组的关键 可导致免疫反应的激活。糖基化也参与细胞机制， 控制TCR活化、免疫细胞运输、TCR和BCR信号传导、抗体功能的阈值，以及 更多.我们假设聚糖在诱导免疫应答或对FVIII耐受中的影响可以 这可能是双重的：一个是糖基化FVIII抗原与宿主免疫系统的相互作用， 聚糖谱在确定诱导抗FVIII免疫应答的风险方面可能是重要的;并且 第二种是外源蛋白或基因的识别和随后的免疫激活 表达可以通过FVIII糖组的不同程度或模式而改变。因此，为了更充分地 了解潜在糖基化对抗FVIII抑制剂开发的影响谱 响应，我们建议首先研究宿主聚糖谱在抗FVIII开发中的影响 在不同背景的人类和小鼠中的反应。接下来，我们将描述免疫 通过递送具有不同糖基化程度或模式的FVIII分子引起的应答， 探讨免疫激活的机制。从这项研究中，我们希望定义特定的免疫学， 通过糖基化及其相关机制触发，导致预防或消除FVIII抑制剂。