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

• 批准号: 8658912
• 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
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8658912
• 关键词: Accounting; Affect; Affinity; Animals; Antibodies; Antibody Formation; 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; Homeostasis; Human; Humoral Immunities; Immune; Immune response; Immunization; Immunoglobulin G; Immunotherapy; Individual; Influenza vaccination; Intervention Studies; Knowledge; Macaca mulatta; Mediating; Minisatellite Repeats; Modeling; Nucleic Acid Regulatory Sequences; Nucleotides; Passive Immunization; 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; in vivo; mouse model; neonatal Fc receptor; pre-clinical; public health relevance; receptor; response; transcytosis; vaccine delivery

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.

产品说明：新生儿Fc受体（FcRn）在体内调节IgG稳态中起重要作用，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对IgG的Fc部分的亲和力决定抗体的血清半衰期。因此，保护性抗体的耐久性可受宿主FcRn功能影响。FcRn的遗传多态性可影响Fc结合[3]，并可能影响IgG的半衰期。因此，我们假设宿主FcRn基因组多态性影响灵长类动物的抗体水平，并可能解释抗体水平的个体间差异。 被动免疫或疫苗接种后的水平。我们的目标是在这个建议是确定功能的宿主基因组多态性的FcRn基因的影响FcRn的表达和功能。特别是，我们想测试基因组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持久性。尚未在任何疫苗研究中评价FcRn基因组变异的影响。我们的努力将测试FcRn功能的疫苗接种研究，使用包膜糖蛋白在恒河猴。使用来自恒河猴的样品（作为资助的临床前疫苗研究的一部分），我们鉴定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。我们研究了FcRn的变体等位基因形式与总IgG和疫苗诱导的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，这对未来的疫苗研究具有相关性。这些知识可以在未来应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诸如Fc融合蛋白或被动抗体转移的策略时。