Anti–PD-L1 therapy to prevent systemic immune suppression after polytraumatic brain injury in rats

BACKGROUND: Trauma is a leading cause of pediatric morbidity and mortality. Children with traumatic brain injury (TBI), especially with extracranial injuries, can develop immune suppression and subsequent infection. Immune checkpoint pathways, for example, programmed death-ligand 1 (PD-L1), may contribute. We hypothesized that an anti–PD-L1 antibody would safely prevent immune suppression in a juvenile rat model of polytraumatic TBI. METHODS: Juvenile rats underwent TBI plus systemic hemorrhage (TBI/H) or sham injury. Rats received daily injections of saline or anti–PD-L1 (10 μg or 100 μg) for 7 days. Systemic immune function was assessed by measuring TNFα production in whole blood and splenocytes after ex vivo stimulation with lipopolysaccharide. Cytokines were measured by ELISA or proteome array. Immunofluorescence was used to quantify microglia, astrocytes, and neurons in postinjury day (PID) 7 brain tissue. Cognitive function was assessed by behavioral testing on PID 1. RESULTS: TBI/H resulted in lower TNFα response in whole blood and spleen ( p =0.02) versus sham-injured rats. TBI/H rats treated with 100 μg anti–PD-L1 had higher TNFα response in whole blood ( p =0.04) and spleen ( p =0.02) versus TBI/H rats treated with saline. Lower dose anti–PD-L1 had no effect on immune function. Unstimulated plasma was examined using a proteome array, and higher levels of inflammatory mediators were noted on PID 7 in injured animals treated with 100 µg anti–PD-L1 versus saline. The 100 μg anti–PD-L1 group had higher perilesional microglia ( p =0.004) and astrocyte ( p =0.03) counts, as compared with TBI/H+saline. Barnes maze results were not different between injured rats treated with 10 μg anti–PD-L1 versus sham injury, but the 100 μg dose resulted in worse performance ( p =0.007). CONCLUSIONS: Anti–PD-L1 treatment prevented posttraumatic immune suppression but only at a dose that resulted in higher numbers of perilesional microglia and no improvement in spatial memory. As such, PD-L1 blockade may not be a good candidate for safely reversing immune suppression after pediatric TBI. ( J Trauma Acute Care Surg. 2026;00:00-00. Copyright © 2026 The Author(s). Published byWolters Kluwer Health, Inc. on behalf of the American Association for the Surgery of Trauma.) LEVEL OF EVIDENCE: Not applicable (basic science/animal research).