Understanding and Controlling Neuro-immune Interactions Following Traumatic Brain Injury

PROJECT SUMMARY Traumatic brain injury (TBI) affects millions of individuals annually resulting in disrupted neuronal circuitry, persistent neurological deficits, and increased susceptibility to secondary infections. Following TBI, the peripheral immune system (PIS) cells contribute to subsequent neuroinflammation and exacerbate neuropathology by homing to the injured brain, associating with micropathological features, and releasing inflammatory factors. Additionally, following TBI, the injured brain releases damage signals into the blood which alters PIS homeostasis and functionality. Indeed, these adjustments to the PIS can result in chronic immunodeficiency, reduced tissue regenerative capacity, impaired neurological outcomes, and an increased mortality rate. However, the mechanisms and outcomes of how these two organ systems affect one another after trauma has never been investigated in a clinically relevant model of diffuse TBI. Therefore, I propose to quantify the liming, extent, and location of the infiltrating PIS in the brain after TBI, to investigate TBI-induced changes to PIS functionality at baseline and after a clinically relevant immune challenge, and to fabricate a therapeutic treatment strategy that will employ cells of the PIS to modulate TBI-induced neuroinflammation. Specifically, immunomodulatory microparticles will be loaded into infiltrating immune cells and these autologous microparticle-loaded cells will be administered intravenously after TBI. Thereafter, the therapeutic efficacy of these cells will be quantified by characterizing the extent of infiltration, effects on the PIS, and distribution of neuropathology. To complete this work, I propose to utilize a high-fidelity preclinical porcine model of closed-head diffuse TBI - which is the most clinically relevant model of TBI biomechanics in use today - along with comprehensive and quantitative PIS characterization. I hypothesize that infiltrating immune cells will localize with micropathological features, the innate and adaptive PIS will exhibit chronic immunosuppression after TBI, and that neuroinflammation will be mitigated when infiltrating immune cells are loaded with immunomodulatory microparticles. Information gained from this proposal will develop a translationally-relevant treatment strategy for TBI that could improve care of affected individuals and inform basic science questions about neuro-immune interactions. Importantly, this research can only be completed at the University of Pennsylvania and VA Medical Center because of unique resources, equipment, and institutional environment that is not available anywhere else in the world. During this career development award, I will have access the injury device that induces the porcine closed-head diffuse TBI, equipment and assays for comprehensive PIS characterization, immunomodulatory microparticle fabrication, and large animal facilities. This career development award will offer a unique training opportunity, answer basic scientific questions, develop translational immunomodulatory tools, and foster committed mentorship that will cultivate a specialized research niche on neuro-immune interactions that will allow me to transition into an independent researcher.