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.
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.
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