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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 稳态中发挥重要作用，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，保护性抗体的持久性可能受到宿主 FcRn 功能的影响。 FcRn 的遗传多态性会影响 Fc 结合 [3] 并可能影响 IgG 的半衰期。因此，我们假设 FcRn 的宿主基因组多态性影响灵长类动物的抗体水平，并可能解释抗体的个体间变异被动免疫或接种疫苗后的水平。我们本提案的目标是确定 FcRn 基因中影响 FcRn 表达和功能的功能性宿主基因组多态性。特别是，我们想要测试基因组 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抗体的耐久性。任何疫苗研究尚未评估 FcRn 基因组变异的影响。我们的工作将在使用恒河猴包膜糖蛋白的疫苗接种研究中测试 FcRn 功能。使用来自恒河猴的样本（作为资助的临床前疫苗研究的一部分），我们识别了该受体的基因组变异，并测试了 FcRn 的多态性形式对 FcRn 表达的影响。我们研究 FcRn 等位基因变异形式与总 IgG 和疫苗诱导 IgG 水平的关联。拟议的研究有可能确定 FcRn 基因组变异在调节 IgG 水平中的作用，这与未来的疫苗研究相关。这些知识将来可用于选择免疫原和动物群体，特别是当需要少量动物来评估 Fc 融合蛋白或被动抗体转移等策略时。