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Anti-PD-L1 therapy to prevent systemic immune suppression after polytraumatic brain injury in rats
Ghaith A Bahader1, Juan Cardenas Fimbres, Simon D Blum
1Center for Clinical and Translation Research (G.B, M.W.H, E.A.S.), Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio; Department of Pediatrics, Division of Critical Care (J.C.F., M.W.H.), Nationwide Children's Hospital, Columbus, Ohio; College of Medicine (S.D.B.), The Ohio State University, Columbus, Ohio; Department of Surgery, Division of Neurosurgery (E.A.S.), Nationwide Children's Hospital, Columbus, Ohio; Department of Neurosurgery (E.A.S.), College of Medicine, The Ohio State University, Columbus, Ohio.
Insights
Anti-programmed death-ligand 1 (PD-L1) antibody treatment prevented immune suppression in juvenile rats with traumatic brain injury (TBI). However, the effective dose increased brain inflammation and worsened cognitive function, suggesting it
Area of Science:
- Neuroscience
- Immunology
- Trauma Surgery
Background:
- Pediatric trauma, particularly traumatic brain injury (TBI) with extracranial injuries, can lead to immune suppression and increased infection risk.
- Immune checkpoint pathways, such as programmed death-ligand 1 (PD-L1), may play a role in post-TBI immune dysfunction.
- Investigating therapeutic strategies to counteract immune suppression following pediatric TBI is critical.
Purpose of the Study:
- To evaluate the safety and efficacy of an anti-PD-L1 antibody in preventing immune suppression in a juvenile rat model of polytraumatic TBI.
- To assess the impact of anti-PD-L1 treatment on systemic immune function, neuroinflammation, and cognitive performance post-TBI.
Main Methods:
- Juvenile rats subjected to TBI with systemic hemorrhage (TBI/H) or sham injury.
- Daily administration of saline or varying doses of anti-PD-L1 antibody for 7 days.
- Assessment of systemic immune function (TNFα production), cytokine profiles, neuroinflammation (microglia, astrocytes, neurons), and cognitive function (Barnes maze).
Main Results:
- TBI/H induced significant immune suppression, evidenced by reduced TNFα response.
- Treatment with a high dose (100 μg) of anti-PD-L1 restored TNFα production but increased inflammatory mediators and glial cell counts (microglia, astrocytes) in the brain.
- While a lower dose of anti-PD-L1 did not affect immune function, the higher dose impaired spatial memory performance in the Barnes maze.
Conclusions:
- Anti-PD-L1 antibody administration can prevent posttraumatic immune suppression in juvenile rats.
- However, the effective dose is associated with increased neuroinflammation and cognitive deficits.
- PD-L1 blockade may not be a suitable therapeutic strategy for mitigating immune suppression after pediatric TBI due to safety concerns.
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).
