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%的患者出现高滴度、中和性抗因子VIII