The goal of this program is to perform directed investigations into the evolution of lasting, protective Immune responses in humans in order to better understand the requirements of effective vaccines and adjuvants. This application is submitted to obtain funding for a Cooperative Center on Human Immunology at The Rockefeller University. Our program is highly integrated and is based on long-term, productive collaborations between the PIs on defining underlying principles of human immunology, utilizing the infrastructure of the Rockefeller University Hospital, the Zanvil Cohn Vaccine Center and the Rockefeller University Clinical and Translational Science Award (CTSA). The proposed research projects are designed as hypothesis-testing, mechanistic studies, examining novel aspects of the activation and regulation of human immune responses in the context of vaccination against infectious disease. The participating investigators are pioneers in identifying and characterizing basic mechanisms of the human immune response, having contributed to the initial characterizations of the dendritic cell, the diversity of IgG antibody effector functions ad description of Fc receptors as mediators of immunity, the development of the first models for study of the hepatitis C virus and the Identification of multiple HCV receptors. While significant progress in basic immunology research over the last three decades has resulted in numerous medical advances, a much more substantial understanding of coordinated molecular mechanisms involved in eliciting Immunity will be required to enable judicious vaccine design, particularly for diseases for which no vaccines currently exits. The objective of this proposal is o draw on the broad expertise in immunity and infectious diseases within the collaborating laboratories to define the contributions of critical components, such as dendritic cells, T follicuar helper cells, monocytes and immune complexes in the generation and maintenance of effective immune responses to infectious agents.
CCHI studies are based on analyses of samples where volunteers were Immunized or delivered an Immune adjuvant. The FDA approved vaccines to be studied are known to elicit durable immunity and are therefore appropriate for use in studying the molecular underpinnings of effective vaccine responses. Via studies of primary cells and sera taken pre- and post-vaccination or adjuvant administration, hypotheses will be explored with the goal of defining molecular pathways that contribute to formation of protective immunity. Project 1: Role of IgG Fc Glycan Composition in Vaccination Project Leader (PL): Ravetch, Jeffrey DESCRIPTION (provided by applicant): 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 SIGNR1/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.
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.
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