# Immunomodulation and Neuroprotection in Multiple Sclerosis

> **NIH VA I01** · RALPH H JOHNSON VA MEDICAL CENTER · 2024 · —

## Abstract

Multiple sclerosis (MS) is a disabling autoimmune disease affecting individuals in their most productive
years and is also prevalent among US Veterans. MS is caused by abnormal activation of myelin-specific
autoreactive T and B cells and their CNS infiltration. At present, there is no cure for MS and the treatments for
MS involve a diverse array of disease-modifying therapies (DMTs) targeting autoimmunity but with relatively
little or no effects on the CNS disease of MS as the disease progression continues.
Recently, anti-CD20-based B cell-depleting therapy has been approved for the treatment of MS. B cells
participate in the autoimmune process by presenting autoantigens and producing autoantibodies. B cells also
regulate T cell-mediated autoimmune responses by producing effector (IL-6) or regulatory (IL-10) cytokines. B
cell depletion is known to inhibit TH1 and TH17 cell immune responses in MS patients and in its animal models
(experimental autoimmune encephalomyelitis; EAE), a mechanism of B cell depletion therapy. B cell depletion
therapy, however, suffers from potential adverse effects, such as opportunistic infections and the generation
of neutralizing antibodies as well as low efficacy. Mechanistically, anti-CD20-antibodies depleting effector B
cells also deplete the regulatory B cells, thus causing loss of regulatory B cell function for inhibition and
recovery of MS/EAE disease. This underscores the need for a new therapy that selectively inhibits effector/
pathogenic functions of B cells while sparing or promoting regulatory/protective B cell functions.
 Recently, our laboratory reported a novel immunomodulatory mechanism of S-nitrosoglutathione (GSNO;
an endogenous S-nitrosothiol) in the EAE model. GSNO-mediated S-nitrosylation plays a critical role in
physiological nitric oxide (NO) signaling for the regulation of multiple cellular pathways. We reported that
exogenous GSNO or optimization of endogenous GSNO, by blocking its turnover using GSNO reductase
(GSNOR) inhibitor (GSNORi), attenuates the effector T cell (TH17) and effector (IL-6+) B cell functions while
increasing the regulatory T cells (Treg) and regulatory (IL-10+) B cell functions and thus protects against the
EAE disease. Based on this, we propose to investigate the preclinical therapeutic potential of GSNO/GSNORi
(S-nitrosylation)-mediated signaling mechanisms in B and T cell-mediated immunomodulation and their
potential efficacy against CNS disease using the EAE model.
Aim 1 is proposed to evaluate the preclinical therapeutic potentials of GSNOR inhibitors.
Aim 2 is proposed to investigate the mechanisms underlying GSNOR inhibitor-mediated
immunomodulation.
 The present study, based on our original contributions, investigates a novel mechanism of balanced
regulation of regulatory vs. effector functions of B cells under autoimmune disease conditions. We expect that
the proposed study will evaluate the preclinical potential of injectable (N6022) and orally active (N91115)
G...

## Key facts

- **NIH application ID:** 10804814
- **Project number:** 2I01BX002829-09A1
- **Recipient organization:** RALPH H JOHNSON VA MEDICAL CENTER
- **Principal Investigator:** Inderjit Singh
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2015-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10804814

## Citation

> US National Institutes of Health, RePORTER application 10804814, Immunomodulation and Neuroprotection in Multiple Sclerosis (2I01BX002829-09A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10804814. Licensed CC0.

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