权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Center for the Investigation of Factor VIII Inhibitors and Glycosylation

因子 VIII 抑制剂和糖基化研究中心

基本信息

批准号：
10227911
负责人：
Lei Li
金额：
$ 134.67万
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/10227911
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

PROJECT 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 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.

项目总结