Reversal of Immunoparalysis Following Traumatic Brain Injury and Systemic Hemorrhage in a Juvenile Rat Model

PROJECT SUMMARY/ABSTRACT Critical injury, including traumatic brain injury (TBI), remains one of the most common causes of morbidity and mortality in children. Despite efforts to develop pharmacotherapy for TBI, clinical trials have proven ineffective. Improvements in outcome have largely been due to improvements in medical care. One known complication of severe TBI is nosocomial infection; the incidence may be as high as 50% with mortality as high as 37%. Even in the absence of mortality, infection can lead to secondary brain injury and poor outcomes. One cause for post- injury nosocomial infections is a profound anti-inflammatory response known as immunoparalysis. TBI is strongly associated with immunoparalysis, and more recent data suggest that patients with TBI plus systemic injury (polytrauma) are even more prone to nosocomial infection than patients with either injury alone. One pathway by which this may occur is through a neurally-mediated mechanism known as the cholinergic anti-inflammatory pathway (CAIP), which involves signaling from the brain to splenic leukocytes via the splenic nerve. Attenuation of the CAIP is a potential method for reversing immunoparalysis, but other therapeutic targets include mechanism-independent immunomodulation. Unfortunately, there is little preclinical data examining the timeline for immune suppression following injury or how reversing post-injury immune suppression may affect the injured, recovering brain. The overall goal of this proposal is to develop immunomodulatory approaches to improve outcomes through safe restoration of immune function following critical injury in children. Our central hypothesis is that post-injury immune suppression is an important acute and chronic sequela of critical injury that can be attenuated without negatively impacting neurological outcomes. Experiments will involve using a clinically relevant combined injury model in juvenile rats: an experimentally induced TBI (controlled cortical impact) followed by hemorrhage induced by aspiration of blood from the femoral artery. To perform mechanism-specific attenuation of post-traumatic immunosuppression, we propose using splenic denervation to inhibit the CAIP. As splenic denervation is clinically not practical, we will also use pharmacotherapeutic agents to target the CAIP, including treatment with an α7 nicotinic receptor antagonist (memantine) or a beta-adrenergic antagonist (propranolol). We will also examine mechanism-independent pharmacotherapy of post-traumatic immune suppression using several immunostimulants (GM-CSF, rIL-7, INF ɣ, and anti-PD-1). Finally, as the long-term immunologic effects of severe traumatic injury are poorly understood, we will quantify the persistence of immunosuppressive effects of severe trauma in both our TBI/H model and in critically injured children. This career development award will generate further preliminary data and provide me with the necessary tools to obtain research independence and further funding in the area of pediatric neurotrauma.