# Novel immune therapy to promote functional recovery after traumatic brain injury

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

Traumatic brain injury (TBI) leads to high mortality and morbidity amongst veterans and civilians. There
is an urgent unmet need for therapies to alleviate the long-term neurological deficits after TBI. Innate (microglia
and macrophages) and adaptive (T and B lymphocytes) immune cells play critical roles in neuroinflammation,
injury progression, and brain repair. Microglia/macrophages are highly plastic cells that execute both beneficial
and detrimental functions after injury. Our previous studies highlight a shift of microglia/macrophages at the
chronic stages of TBI toward a neurotoxic, pro-inflammatory phenotype that impairs tissue preservation and
brain repair. Therefore, identification of mechanisms underlying anti-inflammatory/reparative
microglia/macrophage responses may reveal novel therapeutic targets to foster a microenvironment permissive
for brain repair and long-term recovery after TBI.
 CD4+CD25+ regulatory T cells (Tregs) are a specialized subpopulation of T cells known to alleviate
inflammation. We reported that Tregs exerted neuroprotection by targeting inflammatory dysregulation in stroke.
The effects of Tregs in TBI have not been appreciated until recently, and their mechanism of action is unknown.
We recently in vitro study show that Tregs activated by brain injury stimulate microglial polarization toward an
anti-inflammatory/reparative phenotype, which in turn promotes oligodendrocyte differentiation and maturation.
Using the controlled cortical impact model of TBI, we have obtained in vivo data showing that: 1) Selective Treg
depletion further deteriorates long-term sensorimotor and cognitive functional deficits and exacerbates brain
lesions in both white matter and gray matter up to 21 days after TBI. 2) Treg-depleted mice display worse cerebral
inflammation and more aggressive pro-inflammatory microglia/macrophage responses after TBI. 3) In contrast,
boosting Tregs using an IL-2/IL-2 antibody complex (IL-2/IL-2Ab) significantly reduces brain injury and improves
neurological functions after TBI. Given these new observations, the proposed studies will be the first to test the
mechanistic hypothesis that Tregs improve brain repair and promote long-term recovery after TBI by
polarizing microglia/macrophages toward an inflammation-resolving and reparative phenotype.
 Three Aims will be completed in a systematic fashion. Aim 1. Test if Tregs improve gray and white matter
integrity and enhance long-term functional recovery after TBI. Aim 2. Test if Tregs shift microglia/macrophages
toward an inflammation-resolving and tissue-reparative phenotype after TBI. Aim 3. Test if in vivo expansion of
Tregs with IL-2/IL-2Ab treatment post-TBI reduces brain lesions and improves long-term neurological recovery.
 This study will be the first to mechanistically define the role of Tregs in regulating microglia/macrophage
responses after TBI and to test the therapeutic potential of IL-2/IL-2Ab in TBI. If successful, these studies may
reveal a ne...

## Key facts

- **NIH application ID:** 10721338
- **Project number:** 5I01BX005589-02
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Xiaoming Hu
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-10-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10721338

## Citation

> US National Institutes of Health, RePORTER application 10721338, Novel immune therapy to promote functional recovery after traumatic brain injury (5I01BX005589-02). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10721338. Licensed CC0.

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