Introduction: Trauma is a leading cause of pediatric morbidity and mortality. We have shown that children with traumatic brain injury (TBI), especially with extracranial injuries, can develop severe immune suppression, with increased risk of infection. Immune checkpoint pathways, e.g. programmed death-ligand 1 (PD-L1), may contribute. We hypothesize that anti-PD-L1 antibody will safely prevent immune suppression in a juvenile rat model of TBI with polytrauma. Methods: Juvenile rats underwent TBI + systemic hemorrhage (TBI/H) or sham injury ± anti-PD-L1. Rats received daily injections of saline or anti-PD-L1 (10μg or 100μg) for 7 days, with first dose immediately after injury. Systemic immune function was assessed by measuring TNFα production capacity in whole blood and splenocytes after ex vivo stimulation with lipopolysaccharide (TNFα response). Lower TNFα response indicates greater immune suppression. Immunofluorescence was used to quantify microglia, astrocytes, and neurons in post-injury day (PID) 7 brain tissue. Cognitive function was assessed by Barnes Maze on PID1. Cytokines were measured by ELISA or proteome array. Results: TBI/H resulted in lower TNFα response in whole blood (113pg/ml vs 254pg/ml, p=0.02) and spleen (202pg/ml vs 407pg/ml, p< 0.001) on PID7 vs sham injured rats. TBI/H rats treated with 100 μg anti-PD-L1 had higher TNFα response in whole blood (235pg/ml vs 113pg/ml, p=0.046) and spleen (337pg/ml vs 202pg/ml, p=0.02) vs TBI/H+saline rats. Lower dose anti-PD-L1 had no effect on immune function. Unstimulated plasma had higher levels of inflammatory mediators on PID7 after 100µg anti-PD-L1 vs TBI/H+saline (ICAM-1, IL-1α, and MIP-1α all p< 0.001). The 100μg anti-PD-L1 group had higher peri-lesional microglia (p< 0.001) and astrocyte (p=0.03) counts vs TBI/H+saline, with no difference in neuronal density. Barnes Maze results were not different between injured rats treated with 10μg anti-PD-L1 vs control, but the 100μg dose resulted in worse performance (160% greater escape latency, p= 0.007). Conclusions: High-dose anti-PD-L1 prevented post-trauma immune suppression but resulted in systemic inflammation and impaired cognition. PD-L1 blockade may not be a good candidate to safely prevent immune suppression in pediatric TBI.
Cardenas et al. (Sun,) studied this question.