An emerging concept is that resolution of inflammation is a dynamic process crucial in restoring homeostasis, thus preventing chronic inflammation and disease. Newly identified lipid mediators, derived from polyunsaturated fatty acids (PUFA) are now recognized as crucial players in resolving inflammation. These endogenous specialized proresolution mediators (SPM) constitute separate families including lipoxins, resolvins, protectins and maresins. SPM have newly discovered abilities to regulate cells of the immune system. The humoral response is essential for protection against microorganisms, however the role of SPM in humoral immunity and their effect on B cells has not yet been studied. This is an important knowledge gap. Our new pilot data in support of this R21 application show that SPM have an important ability to enhance mitogen and antigen-driven antibody responses. These results support our hypothesis that the lipid-derived SPM enhance the antibody response to infection by promoting B cell function, leading to improved immune memory and long-term protection. We propose to study the immuno-regulatory functions of SPM on human and mouse B cells and during the adaptive immune response against influenza, in an infection and vaccination pre-clinical model. Adjuvant or """"""""vaccine booster"""""""" properties of SPM could increase vaccine efficacy and utility, permitting smaller doses when a vaccine is poorly immunogenic or in short supply. We propose two specific aims to begin to reveal the function of SPM on B cells.
Aim 1 : Characterize the ability of key SPM to stimulate human B cell antibody production. B cells will be activated with TLR and BCR ligands along with selected SPM. IgM and IgG antibody levels will be determined along with B cell phenotype, survival and proliferation analyses. We will study B cell memory responses using seasonal influenza-vaccinated human subjects. These studies will determine the effects of resolvins on memory and antibody-secreting B cell populations.
Aim 2 : Determine the capacity of lead SPM to stimulate protective antibody production in a pre-clinical mouse influenza virus vaccination and infection model. The functions of SPM during an adaptive memory response will be analyzed using a mouse influenza vaccination and infection model. Mice will be vaccinated using the trivalent seasonal flu vaccine, as well as influenza recombinant protein, hemagglutinin (HA), and complemented with or without SPM. IgM and IgG antibody titers will be measured along with the antibodies'inhibitory and neutralizing properties, reflective of a B cell-mediated adaptive response. The stimulatory properties of SPM will be further assessed by challenging immunized mice with live influenza viral strains, including the 2009 H1N1, and monitoring weight loss, survival, and viral titers.

Public Health Relevance

The purpose of this project is to test a new kind of anti-inflammatory stimulant for making antibodies against infectious agents. The lipid stimulants are naturally occurring and we will test their ability to activate antibody forming cells to respond to influenza virus. The goal is to be able to use these stimulants to produce more effective vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI103690-02
Application #
8606727
Study Section
Vaccines Against Microbial Diseases Study Section (VMD)
Program Officer
Ferguson, Stacy E
Project Start
2013-02-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Rochester
Department
Public Health & Prev Medicine
Type
School of Medicine & Dentistry
DUNS #
City
Rochester
State
NY
Country
United States
Zip Code
14627
Kim, Nina; Lannan, Katie L; Thatcher, Thomas H et al. (2018) Lipoxin B4 Enhances Human Memory B Cell Antibody Production via Upregulating Cyclooxygenase-2 Expression. J Immunol 201:3343-3351
Duffney, Parker F; Falsetta, Megan L; Rackow, Ashley R et al. (2018) Key roles for lipid mediators in the adaptive immune response. J Clin Invest 128:2724-2731
Kim, Nina; Thatcher, Thomas H; Sime, Patricia J et al. (2017) Corticosteroids inhibit anti-IgE activities of specialized proresolving mediators on B cells from asthma patients. JCI Insight 2:e88588
Kim, Nina; Ramon, Sesquile; Thatcher, Thomas H et al. (2016) Specialized proresolving mediators (SPMs) inhibit human B-cell IgE production. Eur J Immunol 46:81-91
Ramon, Sesquile; Bancos, Simona; Serhan, Charles N et al. (2014) Lipoxin A? modulates adaptive immunity by decreasing memory B-cell responses via an ALX/FPR2-dependent mechanism. Eur J Immunol 44:357-69
Ramon, Sesquile; Baker, Steven F; Sahler, Julie M et al. (2014) The specialized proresolving mediator 17-HDHA enhances the antibody-mediated immune response against influenza virus: a new class of adjuvant? J Immunol 193:6031-40
Ramon, Sesquile; Woeller, Collynn F; Phipps, Richard P (2013) The influence of Cox-2 and bioactive lipids on hematological cancers. Curr Angiogenes 2:135-142
Ramon, Sesquile; Gao, Fei; Serhan, Charles N et al. (2012) Specialized proresolving mediators enhance human B cell differentiation to antibody-secreting cells. J Immunol 189:1036-42