# Tunable Assembly of Regulatory Immune Signals to Promote Myelin-specific Tolerance

> **NIH VA I01** · BALTIMORE VA MEDICAL CENTER · 2024 · —

## Abstract

During autoimmune disease, the body identifies and attacks “self” molecules. Current therapies are not curative
and require life-long compliance. Further, existing therapies – while beneficial, are broadly acting and can leave
patients immunocompromised. These challenges have sparked great interest in controlling autoimmunity with
vaccine-like specificity to preserve normal immune function. Both pre-clinical and clinical studies are testing this
idea in multiple sclerosis (MS), a disease that disproportionality impacts Veterans. MS is a neurodegenerative
disease driven by mistaken attack of myelin in the central nervous system (CNS). Thus, an experimental therapy
idea involves co-administration of myelin peptide and tolerizing cues to promote myelin-specific regulatory T
cells (TREG) that control MS. In some recent trials, small sets of 6-8 myelin epitopes are being tested as a route
to span the range of myelin reactivity in many - though not all - patients. Interestingly, one set of pathways newly-
associated with myelin-driven inflammation are toll-like receptors (TLRs). In healthy people, TLRs detect
pathogen-associated patterns to mobilize innate immunity. However, new work shows TLR signaling - such as
TLR9 - is elevated in MS patients and MS models (e.g., EAE, RR-EAE). In the latter, suppressing TLR9 function
reduces inflammation, while also promoting TREG and improving disease. Lymph nodes (LNs) and spleen are
key tissues that control polarization of myelin-reactive T cells toward either inflammatory T cells (e.g., TH17) or
TREG. Thus, strategies that guide T cell differentiating when myelin is presented in LNs – for example, co-delivery
of regulatory cues – could generate large populations of myelin-specific TREG that stop pathogenic immune cells
without broad suppression. Nanotechnology offers unique capabilities for this goal, including co-delivery of self-
antigen and regulatory cues, targeting, and tunable release. However, many polymer particles and other
biomaterials exhibit intrinsic features that trigger inflammatory signaling, which could exacerbate autoimmunity.
Strategies that mimic attractive features of biomaterials, while eliminating inflammatory “carrier” effects could be
transformative for new therapies for MS. This Renewal VA Merit application uses polyionic immune signals to
advance novel nanostructured capsules built entirely from regulatory immune cues and myelin antigen. These
immune polyelectrolyte multilayers (“iPEMs”) are assembled through electrostatic interactions on a template,
which is removed to leave capsules that juxtapose myelin with a regulatory TLR ligand against TLR9 (GpG).
Since there is no carrier, the density of signals in iPEMs is very high relative to polymer or lipids encapsulating
cargo (e.g., nanoparticles). During the initial award, this high density juxtaposition of self-antigen and regulatory
cue (GpG) was shown to promote differentiation of myelin-specific T cells toward TREG and away from
in...

## Key facts

- **NIH application ID:** 10720897
- **Project number:** 5I01BX003690-07
- **Recipient organization:** BALTIMORE VA MEDICAL CENTER
- **Principal Investigator:** Christopher M Jewell
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-07-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10720897

## Citation

> US National Institutes of Health, RePORTER application 10720897, Tunable Assembly of Regulatory Immune Signals to Promote Myelin-specific Tolerance (5I01BX003690-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10720897. Licensed CC0.

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