# Immunoregulation of Myelin-Specific T Lymphocytes

> **NIH VA I01** · PORTLAND VA MEDICAL CENTER · 2020 · —

## Abstract

Multiple sclerosis (MS) and its murine model, experimental autoimmune encephalomyelitis (EAE), are chronic,
debilitating autoimmune diseases of the central nervous system (CNS) characterized by extensive
demyelination and axonal damage. One of the key cytokines thought to drive the early inflammatory stage of
MS to a chonic progressive phase is Macrophage Migration Inhibitory Factor (MIF-1), the first described
cytokine/chemokine. MIF-1 levels are increased in MS and this key factor has been implicated as a marker of
clinical worsening in MS and as a requirement for disease progression in EAE. Our laboratory designed a
potent biological construct called RTL1000 and a second generation derivative, DRα1-MOG-35-55, that bind
tightly to the MIF-1 receptor, CD74, and competitively inhibit MIF-1 binding and downstream signaling.
Recently, a second ligand for CD74 that is an ancestral functional homolog of MIF-1, called D-dopachrome
tautamerase (DDT or MIF-2) was reported. The MIF-2 protein has only 35% homology with MIF-1 and is
expressed at equivalent levels in most tissues. MIF-2 biological activities still require binding to CD74 and
strongly overlap with those of MIF-1, requiring assessment of both MIF-1 and MIF-2 when evaluating MIF
pathogenic activity. We have demonstrated previously that partial MHC class II constructs, including RTL1000
and DRα1-MOG-35-55 have potent therapeutic activity in EAE both are predicted to bind selectively to the
same CD74 trimerization domain residues as MIF-1. However, it remains unstudied whether MIF-2 binds to
these same regions of CD74 or if MIF-2 can be competitively inhibited by RTL1000 and DRα1-MOG-35-55.
Based on our modeling data, we hypothesize that a common region of CD74 binds to distinct regions of the
MIF-1 vs. MIF-2 homotrimers and that RTL1000 and DRα1-MOG-35-55 will competitively block binding and
downstream signaling of both MIF-1 and MIF-2. This proposal will thus address the following Aims: Aim 1:
Determine the effects on MIF-1 and MIF-2 binding and signaling using mutated CD74 constructs and
interfering peptides based on predicted binding interactions. Aim 2: Compare the contributions of MIF-1 vs.
MIF-2 on the onset, severity and progression of EAE in WT, MIF-1K, MIF-2KO and MIF double KO C57BL/6
mice. Aim 3: Test the ability of RTL1000 and DRα1-MOG-35-55 constructs to inhibit MIF-1 vs. MIF-2 binding
and downstream signaling and to treat acute and chronic EAE in MIF-1KO, MIF-2KO and MIF double KO mice
vs. WT mice. These studies will establish if RTL1000 and DRα1-MOG-35-55 can also competitively inhibit
MIF-2 as well as MIF-1 disease-promoting effects in EAE through blockade of CD74-mediated signaling.
Development of these novel therapeutic agents for MS could have a significant impact on the
treatment of MS, which remains an important clinical problem for the VA.
Version: 2-14-16

## Key facts

- **NIH application ID:** 9859295
- **Project number:** 5I01BX000226-12
- **Recipient organization:** PORTLAND VA MEDICAL CENTER
- **Principal Investigator:** ARTHUR A. VANDENBARK
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2009-04-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859295

## Citation

> US National Institutes of Health, RePORTER application 9859295, Immunoregulation of Myelin-Specific T Lymphocytes (5I01BX000226-12). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9859295. Licensed CC0.

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