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.

Public Health Relevance

Neonatal Fc receptor (FcRn) plays important role in regulating IgG half-life in vivo and host genetic polymorphisms in FcRn can influence the half-life of vaccine induced or passively transferred antibodies. In this proposal we identify functional host genomic polymorphisms in the FcRn gene from a large group of rhesus macaques in an ongoing HIV gp120 based vaccine study and test their association with vaccine induced IgG levels. Additionally, data from the present study will assist in proposing future mechanistic studies on variant FcRn binding to IgG as well as on relevance of FcRn polymorphisms for immunological functions of FcRn like antigen presentation and antigen transcytosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Research Grants (R03)
Project #
1R03AI110229-01
Application #
8658912
Study Section
HIV/AIDS Vaccines Study Section (VACC)
Program Officer
Warren, Jon T
Project Start
2014-06-15
Project End
2016-05-31
Budget Start
2014-06-15
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$76,750
Indirect Cost
$26,750
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201