# Immunoregulatory effect of microparticle delivered STING agonist in the control of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS)

> **NIH NIH R21** · THOMAS JEFFERSON UNIVERSITY · 2021 · $234,966

## Abstract

While multiple antiinflammatory therapies are effective in suppressing relapsing-remitting multiple sclerosis
(RRMS) disease progression, they have significant side effects and toxicity. We are still seeking a disease
specific treatment that would provide an antigen-specific immune tolerance reconstitution. We used
microparticle (MP)-encapsulated STING agonist cGAMP to increase its delivery into phagocytic antigen
presenting cells (APCs), particularly dendritic cells (DCs). A novel acid-sensitive polymer, acetalated dextran
(Ace-DEX) allows regulated MP breakdown due to its pH sensitivity in intracellular acidic compartments. Our
preliminary data have demonstrated that the intracellular delivery of MPs encapsulating 2’3’cyclic GMP-AMP
dinucleotide (cGAMP) suppressed experimental autoimmune encephalomyelitis (EAE), an animal model of MS,
when administered before and at the peak of clinical disease. The therapeutic effect of cGAMP MPs in RR and
chronic EAE was mediated via STING-induced IL-27 and IL-10 production, since the therapeutic effect was
abrogated in IL-27ra-/- and IL-10-/- mice, while partial disease suppression was maintained in Ifnar-/- mice. Our
central hypothesis is that intracellular cGAMP MP delivery will induce IL-27 and IL-10-producing tolerogenic
DCs that regulate the differentiation and expansion of IL-10-producing iTregs. We will characterize cGAMP MP
tolerogenic DC phenotype and function, as well as suppressive capacity of the induced regulatory CD4+IL-10+
cells, in particular their expression of FoxP3 and type 1 iTreg (Tr1) markers. We propose that presentation of
MHC class II DR2-anchored peptide mixtures (DR2-APMs) by cGAMP MP-induced tolerogenic DCs from DR2+
patients with relapsing remitting multiple sclerosis (RRMS) may reconstitute antigen-specific immune tolerance.
In order to identify the mechanisms of cAMP MP-mediated disease suppression, we will pursue following
specific aims: 1) Demonstrate that cGAMP MP treatment induces iTreg cell expansion in EAE. The
proposed studies will determine to what extent cGAMP MP treatment of EAE induces the expansion of
CD4+CD25+IL-27R+IL-10+ Tregs in the peripheral immune organs and the CNS inflammatory infiltrates. Studies
using aCD25mAb will confirm the role of iTregs in the therapeutic effect. The role of FoxP3+Tregs will be
examined using transient inducible FoxP3+Treg depletion and mice with selective FoxP3+Treg IL-27R depletion.
2) In human in-vitro studies, we will characterize cGAMP MP-induced tolerogenic DCs and their capacity
to induce iTregs in RRMS patients. Specific experiments will determine the capacity of cGAMP MP-treated
monocytes and DCs to induce iTreg expansion, determine the transcriptome of cGAMP MP IL-27- and IL-10-
induced Tregs and the reconstitution of their suppressive capacity. Finally, co-administration of cGAMP MPs
with DR2-APMs to DCs from RRMS patients will test their capacity to induce antigen-specific tolerogenic DCs
and Tregs. The study will provide...

## Key facts

- **NIH application ID:** 10143635
- **Project number:** 1R21AI154772-01A1
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Silva Markovic-Plese
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $234,966
- **Award type:** 1
- **Project period:** 2021-04-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10143635

## Citation

> US National Institutes of Health, RePORTER application 10143635, Immunoregulatory effect of microparticle delivered STING agonist in the control of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) (1R21AI154772-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10143635. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*