# BLR&D Research Career Scientist Award Application

> **NIH VA IK6** · PORTLAND VA MEDICAL CENTER · 2020 · —

## Abstract

The mission of my Neuroimmunology Research Program is to develop a deep biological understanding of
autoimmune, demyelinating and neurodegenerative processes that affect the central nervous system (CNS)
and to identify and test novel disease-relevant therapies that can be brought to market to treat and/or cure
these conditions. Veterans are currently developing intractable chronic neurological diseases such as multiple
sclerosis (MS) and stroke, service related injuries including traumatic brain injury (TBI) and post-traumatic
stress disorder (PTSD), and substance abuse of alcohol and methamphetamine. Studies carried out by our
laboratory are highly relevant to these devastating conditions due to our development of a novel therapy that
targets a common underlying mechanism, the MIF/CD74 axis that promotes chronic inflammation in the CNS
and other tissues. MIF (macrophage migration inhibitory factor) and its homolog D-DT (D-dopachrome
tautomerase) are highly inflammatory cytokines that trigger release of other inflammatory factors upon binding
and signaling through their common receptor, CD74, a chaperone for loading self and foreign peptides into
MHC class II molecules on antigen presenting cells (APC). The result of MIF/CD74 signaling is peptide-specific
Teffector cell activation and recruitment of inflammatory cells from blood into the CNS. Our initial unique
therapeutic construct, called RTL1000 is comprised of linked DRα1 and DRβ1 domains of HLA-DR2 (an MS
risk factor) covalently linked to myelin oligodendrocyte glycoprotein (MOG) 35-55. This construct has
conformational similarity to naturally occurring MHC class II/peptide T cell receptor ligands, but induces T cell
tolerance when present in soluble form without cell-bound co-stimulatory molecules on APC. This construct
has immunoregulatory and neuroprotective properties in a mouse model of MS (experimental autoimmune
encephalomyelitis, EAE) and was shown to be safe and well tolerated in a Phase 1 study in MS. RTL1000 will
soon be tested in a multi-dose MS clinical trial. The major breakthrough in understanding the potent effects of
RTL1000 occurred in 2013 with the discovery of CD74 as the cellular receptor for RTL1000. This led to the
unifying discovery that RTL1000 could competitively inhibit binding of both MIF and D-DT to CD74 and thus
short-circuit MIF/CD74 signaling that is present in essentially all of the VA targeted CNS conditions. Molecular
modeling of MIF binding revealed two discrete CD74 regions that bound to homologous sequences on MIF and
D-DT and to the DRα1 moiety of RTL1000, thus explaining RTL1000’s competitive inhibition. However,
RTL1000 can only be used in ~60% of MS subjects that express HLA-DR2. We thus designed a new
construct, DRα1-MOG-35-55 that retained the activities of RTL1000 and could modulate CD74 and
competitively block MIF binding, resulting in a significant treatment effect and neuroprotection in chronic EAE.
Of interest, RTL1000 and DRα1-MOG-35-55 were ...

## Key facts

- **NIH application ID:** 9899089
- **Project number:** 5IK6BX004209-03
- **Recipient organization:** PORTLAND VA MEDICAL CENTER
- **Principal Investigator:** ARTHUR A. VANDENBARK
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899089

## Citation

> US National Institutes of Health, RePORTER application 9899089, BLR&D Research Career Scientist Award Application (5IK6BX004209-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9899089. Licensed CC0.

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