# Immunoregulation of Myelin Specific T Lymphocytes

> **NIH VA I01** · PORTLAND VA MEDICAL CENTER · 2021 · —

## Abstract

Multiple sclerosis (MS) is a devastating chronic, demyelinating autoimmune diseases of the central nervous
system (CNS). Two key cytokines/chemokines thought to drive the early inflammatory stage of MS to a chronic
progressive phase are macrophage Migration Inhibitory Factor (MIF) and its homolog D-Dopachrome
Tautomerase (D-DT). Our laboratory designed two potent biological constructs called RTL1000 and a second-
generation derivative, DRα1-MOG-35-55, that bind tightly to the MIF receptor, CD74, and competitively inhibit
MIF binding and downstream signaling through phosphorylated extracellular-related kinase (pERK1/2).
RTL1000/DRα1-MOG-35-55 also targets T cell receptors resulting in the inhibition of IL-2 release, T cell and
macrophage activation and their migration into the CNS. Treatment of mice with experimental autoimmune
encephalomyelitis (EAE – an animal model of MS) with DRα1-MOG-35-55 reduces the severity of both the acute
and chronic forms of the disease when administered after onset of clinical signs and also promotes
neuroprotection. New findings obtained during the previous Merit Review funding period have established
several key facts that provide a solid basis for the studies proposed in this resubmission, including: 1) Detailed
understanding of MIF and D-DT molecular interactions with their common receptor, CD74 and their contributions
to acute and chronic EAE disease severity; 2) Discovery and characterization of DRQ, an ~8-fold more potent
variant of DRα1-MOG-35-55 called DRhQ, [DRα1(L50Q)-human (h)MOG-35-55] for human clinical trials and its
homolog, DRmQ, [DRα1(L50Q)-mouse (m)MOG-35-55] that was created for use in rodents; and 3) Demonstration
that DRmQ treatment of acute and chronic EAE not only blocks signaling through the MIF/CD74 axis and the T
cell receptor, but also inhibits additional proinflammatory pathways and promotes neuroprotection. The
hypothesis to be addressed in this renewal application is that DRQ can inhibit inflammatory innate and adaptive
immune pathways and simultaneously stimulate remyelination and neuronal protection. The major goals of the
current grant application are to evaluate possible proinflammatory interactions between the MIF/CD74 axis with
the triggering receptor expressed on myeloid cells-1 (TREM-1) pathway in EAE; and to determine if DRmQ can
block TREM-1, CXCR2 (which inhibits oligodendrocyte precursor proliferation) and the TCR and simultaneously
enhance three neuroprotective pathways involving TREM-2 and several chemokine ligand and receptor pairs
that were implicated in cytokine/chemokine screening studies. This triad spectrum of DRQ inhibition of
MIF/CD74, TREM-1 and encephalitogenic T cell activity coupled with its stimulatory effects on CNS remyelination
and axonal health in EAE will validate the unique therapeutic potential of DRhQ for MS and allow this novel
“designer” drug to compete favorably with current and future monoclonal antibody and other currently approved
therapies for MS...

## Key facts

- **NIH application ID:** 10125504
- **Project number:** 2I01BX000226-13
- **Recipient organization:** PORTLAND VA MEDICAL CENTER
- **Principal Investigator:** ARTHUR A. VANDENBARK
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2009-04-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10125504

## Citation

> US National Institutes of Health, RePORTER application 10125504, Immunoregulation of Myelin Specific T Lymphocytes (2I01BX000226-13). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10125504. Licensed CC0.

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