# Biomaterials to study tolerance immune induction kinetics

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $376,558

## Abstract

ABSTRACT
We plan to explore the kinetics of the immune synapse, as it relates to generation of tolerance, using
nano/microparticles (Ps) fabricated from the polymer acetalated dextran (Ac-DEX). Previously, we have shown
attenuation of clinical score with treatment of Ac-DEX particles encapsulating myelin basic protein (MBP) and
dexamethasone (DXM), using a C57Bl/6 mouse model of experimental autoimmune encephalomyelitis (EAE).
We continued this research and illustrated that Ac-DEX particles encapsulating proteolipid protein (PLP) and
rapamycin (Rapa) in a SJL relapse and remitting model of EAE completely reduced clinical score to baseline
when given after disease onset. The degree of reduction of clinical score for both of these EAE models was
greater for the Ac-DEX particles systems than observed in other published antigen-specific EAE treatments that
used particle systems. Our particle system is unique because it relies on the highly tunable polymer Ac-DEX.
Ac-DEX is ideal for delivery of agents to phagocytic cells because it is acid-sensitive and has significantly
increased degradation in the low acid (~pH 5) of the phagosome. In addition to this it has tunable degradation
rates that can range from hours to months, which is a unique range from commonly used polyesters (e.g.
poly(lactic-co-glycolic acid) (PLGA)) that have degradation on the order of months. Moreover, Ac-DEX is unique
from polyesters because its degradation products are pH neutral, and do not have the potential to shift the local
pH or damage sensitive payloads. We have shown that Ac-DEX particles have degradation rates that affect both
antibody and cellular response for traditional vaccine and hypothesize similar effects for generation of tolerance.
Therefore, we hypothesize that Ac-DEX particles promote antigen specific immune tolerance by inducing Tregs
and that the cyclic acetal coverage of Ac-DEX impact degradation rate and modulate the immune synapse. We
have three specific aims to address this hypothesis. Aim 1 is focused on formulation of the polymer and particles.
Both a MS representative antigen as well as the model antigen OVA will be encapsulated. Particle parameters
like size and loading will be determined. Ac-DEX polymer with various cyclic acetal coverages will be fabricated
to degrade over a broad range of times. Aim 2 focuses on in vitro and in vivo studies to understand the immune
synapse and how that relates to particle degradation times. The metrics for evaluation will be generation of
inducible T-regulatory cells (iTregs). Furthermore, we will optimize systems using a delayed type hypersensitivity
(DTH) model of inflammation. The relationship between particle degradation and generation of tolerance will be
optimized. In Aim 3, the optimized formulation will be evaluated in a model of MS and expression of Tregs, as well
as other immunological characterizations will be carried out. The overall goal of this work is to evaluate the Ac-
DEX particles systems as a...

## Key facts

- **NIH application ID:** 9979740
- **Project number:** 5R01AI137525-03
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Kristy M Ainslie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,558
- **Award type:** 5
- **Project period:** 2018-08-14 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979740

## Citation

> US National Institutes of Health, RePORTER application 9979740, Biomaterials to study tolerance immune induction kinetics (5R01AI137525-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9979740. Licensed CC0.

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