Genetic Polymorphisms in Rhesus Macaque FcRn and Association with IgG Levels

恒河猴 FcRn 的遗传多态性及其与 IgG 水平的关联

基本信息

批准号：
8867139
负责人：
Bhawna Poonia
金额：
$ 7.68万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8867139
关键词：
Accounting Affect Affinity Animals Antibodies Antibody Response Antigen Presentation Antigen-Antibody Complex Antigens Attenuated Vaccines Binding Biological Assay Chimeric Proteins Code Data Epithelial Cells Epithelium Fc Receptor Funding Future Genes Genetic Polymorphism Genomics Genotype Glycoproteins Goals HIV HIV Envelope Protein gp120 HIV vaccine Half-Life Haplotypes Health Homeostasis Human Humoral Immunities Immune Immune response Immunization Immunoglobulin G Individual Influenza vaccination Intervention Studies Knowledge Macaca mulatta Mediating Minisatellite Repeats Modeling Nucleic Acid Regulatory Sequences Nucleotides Passive Immunization Passive Immunotherapy Passive Transfer of Immunity Play Primates Promoter Regions Receptor Gene Reporting Role Sampling Serum Stretching Testing Therapeutic Transgenic Mice Vaccination Vaccines Variant Virus base cohort design genetic variant genomic variation in vivo mouse model neonatal Fc receptor pre-clinical receptor response transcytosis vaccine delivery vaccine evaluation vaccine trial

项目摘要

DESCRIPTION: Neonatal Fc receptor (FcRn) plays important role in regulating IgG homeostasis in vivo and it's expression level is shown to correlate with vaccine induced antibody levels in transgenic mouse model [1, 2]. The affinity of FcRn to Fc portion of IgG determines serum half-life of antibodies. Durability of protective antibodies can thus, be influenced by host FcRn function. Genetic polymorphisms in FcRn can affect Fc binding [3] and possibly half-life of IgG. Therefore, we hypothesize that host genomic polymorphisms in FcRn influence antibody levels in primates and might account for inter-individual variations in antibody levels upon passive immunization or vaccination. Our goal in this proposal is to identify functional host genomic polymorphisms in the FcRn gene that influence FcRn expression and function. In particular, we want to test the possibility that genomic FcRn polymorphisms influence levels of serum IgG. Such function of FcRn will influence the durability of vaccine-induced antibodies. An effect of FcRn genomic variations has not been evaluated in any vaccine study. Our efforts will test FcRn function in a vaccination study that uses envelope glycoprotein in rhesus macaques. Using samples from rhesus macaques (as part of a funded preclinical vaccine study), we identify genomic variations in this receptor and test the polymorphic forms of FcRn for their influence on FcRn expression. We study association of variant allelic forms of FcRn with levels of total and vaccine induced IgG. The proposed studies have the potential to identify role of genomic variations in FcRn in regulating IgG levels, which have relevance for future vaccine studies. The knowledge can be applied in future to select immunogens and animal groups, especially when small numbers of animals are needed for evaluating strategies such as Fc-fusion proteins or passive antibody transfers.

描述：新生儿FC受体（FCRN）在调节体内IgG稳态中起重要作用，并且其表达水平与转基因小鼠模型中疫苗诱导的抗体水平相关[1，2]。 FCRN与IgG FC部分的亲和力决定了抗体的血清半衰期。因此，保护性抗体的耐用性可能会受到宿主FCRN功能的影响。 FCRN中的遗传多态性会影响FC结合[3]，可能是IgG的半衰期。因此，我们假设FCRN中的宿主基因组多态性会影响灵长类动物的抗体水平，并且可能解释了抗体的个体间变化被动免疫或疫苗接种后的水平。我们在该建议中的目标是确定影响FCRN表达和功能的FCRN基因中的功能性宿主基因组多态性。特别是，我们希望测试基因组FCRN多态性影响血清IgG水平的可能性。 FCRN的这种功能将影响疫苗诱导的抗体的耐用性。在任何疫苗研究中尚未评估FCRN基因组变异的影响。我们的努力将在一项疫苗接种研究中测试FCRN功能，该研究在恒河猕猴中使用包膜糖蛋白。使用恒河猕猴的样品（作为资助的临床前疫苗研究的一部分），我们确定了该受体中的基因组变异，并测试了FCRN的多态性形式，以影响其对FCRN表达的影响。我们研究了FCRN变异等位基因形式的关联与总和疫苗诱导的IgG水平的关联。拟议的研究具有鉴定基因组变异在FCRN中的作用，这与未来疫苗研究相关的IgG水平。将来可以将知识应用于选择免疫原子和动物群，尤其是当需要少量动物来评估诸如FC融合蛋白或被动抗体转移等策略时。