As basic mediators of humoral immunity, immunoglobulins have evolved to clear microbes and toxic molecules through coupling of antigen specificity to Fc-mediated effector functions. Effector functions conferred through the Fc domain include positive regulatory mechanisms such as the activation of antibody-dependent cellular cytotoxicity, phagocytosis, or pro-inflammatory cytokine production, as well as negative regulatory functions, such as inhibition of inflammatory immune responses. Whether activity mediated by the Fc region is pro- or anti-Inflammatory in nature Is determined by Fc protein sequence and by the precise composition of an N-linked, complex, biantennary glycan that regulates interactions with members of the IgG Fc receptor family (FcyRs) the SIGN family of molecules (mouse SIGNRI/human DC-SIGN) and CD23. The composition of the core Fc glycan can be altered by addition of saccharide units (fucose, Nacetylglucosamine, galactose and sialic acid) and these modifications directly alter the biological activity of IgG molecules. Though the precise saccharide composition of Fc glycans is a known determinant of the biological activity of IgGs, little is known about regulation of Fc glycan composition. Interestingly, vaccination of mice and of humans has been observed to cause various modulations in IgG Fc glycan composition. That Fc glycan composition can be modulated by vaccination is Intriguing as it offers a system by which to study specific factors as they may or may not have a role In regulation; for example, glycan modifications might be determined by the nature/T cell dependence of the antigen, the route of antigen exposure, or host factors such as age. We propose to conduct the first systematic study of vaccine-elicited Fc glycan modifications in humans by Immunization of volunteers with a panel of FDA vaccines. The experiments proposed in this application are designed to investigate two basic hypotheses: 1) that the composition of Fc glycans is actively regulated, and 2) that Fc glycan composition, either In the pre-existing IgG pool or on newly elicited IgGs directs the maturation of a humoral immune response.

Public Health Relevance

The proposed project is designed to Identify factors involved In the regulation of IgG Fc glycan composition and to Investigate a role for the Fc glycan in determining vaccine efficacy in humans. Data from these studies may contribute to our understanding of Inflammatory diseases and inform the design of new vaccines, adjuvants and enhanced monoclonal antibody therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI111825-05
Application #
9631980
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Ramachandra, Lakshmi
Project Start
Project End
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Rockefeller University
Department
Type
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
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