Vaccines for immunological defense against traumatic brain injury

Abstract

Traumatic brain injury (TBI) and subsequent neurodegeneration is partially driven by chronic inflammation both locally and systemically. Yet, current clinical intervention strategies do not mitigate inflammation sequalae necessitating the development of innovative approaches to reduce inflammation and minimize deleterious effects of TBI. Herein, a subcutaneous formulation based on polymer of alpha-ketoglutarate (paKG) delivering glycolytic inhibitor PFK15 (PFKFB3 inhibitor, a rate limiting step in glycolysis), alpha-ketoglutarate (to fuel Krebs cycle) and peptide antigen from myelin proteolipid protein (PLP139-151) was utilized as the prophylactic immunosuppressive formulation in a mouse model of TBI. In vitro, the paKG(PFK15+PLP) vaccine formulation stimulated proliferation of immunosuppressive regulatory T cells and induced generation of T helper-2 cells. When given subcutaneously in the periphery to two weeks prior to mice sustaining a TBI, the active vaccine formulation increased frequency of immunosuppressive macrophages and dendritic cells in the periphery and the brain at day 7 post- TBI and by 28 days post-TBI enhanced PLP-specific immunosuppressive cells infiltrated the brain. While immunohistology measurements of neuroinflammation were not altered 28 days post-TBI, the vaccine formulation improved motor function and enhanced autophagy mediated genes in a spatial manner in the brain. Overall, these data suggest that the TBI vaccine formulation successfully induced an anti-inflammatory profile and decreased TBI-associated inflammation. TeaserIn this study, a vaccine formulation was generated to develop central nervous specific immunosuppressive responses for TBI.