# CAR-T cell treatment of CNS Autoimmunity

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $671,939

## Abstract

PROJECT SUMMARY
An immense need for selective and antigen-specific immunotherapy without global immunosuppression exists
for autoimmune diseases such as multiple sclerosis (MS) and a closely related condition known as myelin
oligodendrocyte glycoprotein (MOG) antibody disease (MOGAD). This has prompted exploration of chimeric
antigen receptor (CAR) T cell utilization to specifically eliminate autoreactive cells. We have created a unique
version of CAR T cells in which peptide MHCII (pMHCII) was fused with signaling domains in order to recognize
specific T cell receptors (TCRs). In preliminary studies we demonstrate that these pMHCII-CAR T cells
specifically recognize a cognate TCR in vitro and can selectively kill antigen-specific CD4 T cells in vivo. Efficient
depletion of high affinity MOG-specific CD4 T cells was associated with prevention of MOG-induced experimental
autoimmune encephalomyelitis (EAE), an animal model of MS. Modifications in pMHCII-CAR construction led to
greater efficiency in eliminating lower-affinity MOG-reactive T cells which was associated with resolution of
ongoing EAE. These data suggest an “activation energy” model of autoimmunity analogous to that of a chemical
reaction, in which higher affinity self-reactive T cells are needed to provide the activation energy to initiate
autoimmunity, but lower affinity T cells are capable of sustaining the autoimmune “reaction.” To address the
hypothesis that CAR T cell technology can be used to eliminate auto-antigen-specific T cells and abrogate central
nervous system (CNS) autoimmunity in mice and humans without global immunosuppression, we have
formulated three specific aims. In Aim 1 we will improve the efficiency of low affinity T cell deletion in vivo. In Aim
2, we will test whether we can successfully target autoreactive CD4 T cells specific to all T cell epitopes of a
protein in mice, as we predict that such an approach would be useful for treatment of human disease where the
T cell autoantigen is identified by an autoantibody. Finally, in Aim 3, we will directly test whether MOGAD patients
show an increased frequency of MOG-specific T cells using pMHCII-CARs for antigen discovery. In sum, our
proposed studies will explore the “activation energy” model of autoimmunity and establish an optimal CAR T cell
approach to eliminate low affinity autoreactive TCR specificities for the treatment of ongoing autoimmune disease.
Finally, we will begin to translate these murine observations to human pMHCII-CAR T cells and assess their
potential utility in a relevant human autoimmune CNS disease.

## Key facts

- **NIH application ID:** 10539779
- **Project number:** 1R01AI165771-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** CHYI S HSIEH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $671,939
- **Award type:** 1
- **Project period:** 2022-06-13 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10539779

## Citation

> US National Institutes of Health, RePORTER application 10539779, CAR-T cell treatment of CNS Autoimmunity (1R01AI165771-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10539779. Licensed CC0.

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