The Specialized Proresolving Mediator 17-HDHA Enhances the Antibody-Mediated Immune Response against Influenza Virus: A New Class of Adjuvant?

Abstract

Influenza viruses remain a critical global health concern. More efficacious vaccines are needed to protect against influenza virus, yet few adjuvants are approved for routine use. Specialized proresolving mediators (SPMs) are powerful endogenous bioactive regulators of inflammation, with great clinical translational properties. Here, we investigated the ability of the SPM 17-HDHA to enhance the adaptive immune response using an OVA immunization model and a pre-clinical influenza vaccination mouse model. Our findings revealed that mice immunized with OVA plus 17-HDHA or with H1N1-derived HA protein plus 17-HDHA increased antigen-specific antibody titers. 17-HDHA increased the number of antibody-secreting cells in vitro as well as the number of HA-specific antibody secreting cells present in the bone marrow. Importantly, the 17-HDHA-mediated increased antibody production was more protective against live pH1N1 influenza infection in mice. This is the first report on the biological effects of omega-3-derived SPMs on the humoral immune response. These findings illustrate a previously unknown biological link between proresolution signals and the adaptive immune system. Furthermore, this work has important implications for the understanding of B cell biology, as well as the development of new potential vaccine adjuvants.

Specialized pro-resolving mediators: endogenous regulators of infection and inflammation

“…Of note, MaR1 was recently identified as a potent inducer for the formation of regulatory T cells in vivo and in vitro in combination with TGFβ 70 . Only limited information is available on SPM actions on B cells, but RvD1 was recently shown to augment B cell antibody production and increase the number of antibody-producing B cells in a mouse influenza vaccination model 74 . These emerging data on the regulation of adaptive immunity by SPMs extend their range of actions and suggest a pivotal role for these imunoresolvents in the transition from innate to adaptive inflammation.…”

Short-term consumption of n-3 PUFAs increases murine IL-5 levels, but IL-5 is not the mechanistic link between n-3 fatty acids and changes in B-cell populations

“…Indeed, there is evidence in the literature to show that dietary n-3 PUFA supplementation can increase levels of pro-resolving lipid mediators, although there are some labs that question this possibility [34-36]. Furthermore, Phipps and co-workers have demonstrated that 17-HDHA, a hydroxylated DHA molecule, enhances the production of antibody secreting cells in vitro and in vivo [37, 38]. Therefore, we speculate that metabolo-lipidomics analyses will shed light on how n-3 PUFAs as dietary supplements may be influencing the concentrations of differing specialized pro-resolving lipid mediators and thereby the frequency of B cell subsets.…”

Competitive detection of influenza neutralizing antibodies using a novel bivalent fluorescence-based microneutralization assay (BiFMA)

“…MDCK X31-HA cells were used because the NAbs tested did not have reactivity against group 2 X31 HA. Twenty-four hours post-infection, cells were washed with 1X PBS and analyzed for viral infection using a fluorescence plate reader (DTX-880, Beckman Coulter) as previously described [22, 38, 39]. Percent neutralization was determined as previously described [29].…”

“…To determine virus quantities, MDCK-HA cells were co-infected with five, two-fold serial dilutions (starting inoculum of 2,000 FFU/well) of mRFP and GFP viruses in triplicate, testing all combinations (data not shown), and the conditions that provided the highest signal above background fluorescence at 24 hours post-infection for both viruses was used. BiFMA assays were performed as described above and previously [22, 29, 38, 39]. …”