# Role of T cells in ischemic brain damage

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $329,123

## Abstract

PROJECT SUMMARY/ABSTRACT
Stroke is one of the leading causes of death and disability worldwide and is the third leading cause of death
and disability in the United States. Clinical and preclinical studies suggest the importance of inflammation in
acute and chronic neuronal tissue damage following ischemic stroke; however, the mechanisms and cells
involved in neuroinflammation are not fully understood. There is currently no available treatment for targeting
the acute immune response that develops in the brain during cerebral ischemia, and no new treatment has
been introduced to stroke therapy since the discovery of tissue plasminogen activator therapy in 1996. We
discovered that interleukin 21 (IL21) is a major contributor to acute brain injury after ischemic stroke. IL21
expressing cells were detected in perivascular regions and the infarcted parenchyma of ischemic human brain
tissues. This raises the possibility that IL21–targeting therapies adjunct to current treatments might be
beneficial in stroke management. The long-term goal of this work is to understand how to manipulate the
acute inflammation following ischemic injury in order to inhibit stroke-induced tissue damage. The objective of
this proposal is to define the mechanisms by which pathogenic follicular helper T cells (Tfh) and IL21 are
involved in acute stroke-induced injury. The specific hypothesis is that the recently discovered circulating
pathogenic IL21-producing Tfh cells infiltrate into ischemic tissues in the brain, where IL21 contributes to tissue
damage by inducing neuronal death. Three aims will study how Tfh cells and IL21 contribute to ischemic injury
in the brain. In Aim 1, we will elucidate the pathways that drive IL21-producing Tfh cell infiltration, development
and function in the CNS during different stages of ischemic injury induced by transient Middle Cerebral Artery
Occlusion (tMCAO). We propose that selective Tfh cell recruitment blockers could decrease tissue damage in
stroke. In Aim 2, we will evaluate spatiotemporal expression of IL21R in the ischemic brain and test potential
regulator(s) of IL21R expression on neurons. We propose that inhibiting IL21R expression on neurons could
decrease tissue damage in stroke. In Aim 3, we will characterize the role of IL21R on neurons in the
pathogenesis of ischemic stroke. We will evaluate acute and chronic ischemic damage and the CNS
inflammatory milieu in mice that selectively lack IL21R in neurons.
Successful completion of this work will lead to a better understanding of the mechanism by which
pathogenic IL21-producing cells promote damage in ischemic injury and identify new therapeutic
targets in stroke.

## Key facts

- **NIH application ID:** 9884832
- **Project number:** 5R01NS103506-03
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Zsuzsanna Fabry
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $329,123
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9884832

## Citation

> US National Institutes of Health, RePORTER application 9884832, Role of T cells in ischemic brain damage (5R01NS103506-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9884832. Licensed CC0.

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