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

> **NIH NIH K08** · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · 2024 · $187,635

## Abstract

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 fu...

## Key facts

- **NIH application ID:** 10825441
- **Project number:** 5K08NS119878-03
- **Recipient organization:** RESEARCH INST NATIONWIDE CHILDREN'S HOSP
- **Principal Investigator:** Eric Anthony Sribnick
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $187,635
- **Award type:** 5
- **Project period:** 2022-04-15 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10825441

## Citation

> US National Institutes of Health, RePORTER application 10825441, Reversal of Immunoparalysis Following Traumatic Brain Injury and Systemic Hemorrhage in a Juvenile Rat Model (5K08NS119878-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10825441. Licensed CC0.

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