# DEVELOPMENT OF A REGULATORY T CELL MIMETIC FOR TOLERANCE INDUCTION IN SKIN TRANSPLANTATION

> **NIH NIH R21** · DUQUESNE UNIVERSITY · 2020 · $47,784

## Abstract

In this competitive revision we propose to formulate a second generation of regulatory T cell (Treg) mimetic by
including adenosine (ADO) to the biomaterials system, from muxTIC (TGF-β1, IL-10, and CTLA-4Ig) to
muxTICA. The purpose is to investigate the mechanistic aspects of muxTICA as a locally-delivered (bronchial
instillation) therapeutic for acute respiratory distress syndrome (ARDS). We will test the capacity of the
combined immunosuppressive factors to skew alveolus macrophages to an anti-inflammatory phenotype in a
pro-inflammatory microenvironment. The experiments involve testing the agents in vitro using alveolar
macrophage lines, in human 3D airway epithelial tissues, and in a microfluidic shear cellular system.
The rationale for exploring the immunosuppressive strategy is that COVID-19-induced ARDS is associated
with excessive inflammation, characterized by rapid surges of pro-inflammatory cytokines such as IL-1β, IL-17,
IL-6 and TNFα. The clinical picture akin to the cytokine storm immunopathology reported in the patients
infected with the coronaviruses emerged in 2002 (`SARS”) and 2012 (“MERS”).
Because corticosteroids are
not recommended and might exacerbate COVID-19-associated lung injury, novel immunosuppressive
strategies are urgently needed to mitigate the hyper-inflammation associated with ARDS.
Clinical studies indicate that Tregs can ameliorate ARDS. Survivors of COVID-19 infections have higher
blood-circulating Tregs than non-survivors, and patients with elevated TGF-β1 and IL-10 have better
outcomes. Mechanistically Tregs limit lung fibrosis form infections and inhibit excessive virus-specific T cell
responses. A major driver of ARDS in COVID-19 infected patients is massive infiltration of macrophages
infiltration, which produce pro-inflammatory cytokines and prorogate inflammation, resulting in lung fibrosis and
alveolar edema. Tregs has the capacity to steer macrophages an M2 regulatory, anti-inflammatory phenotype.
In addition to TGF-β1, IL-10, and CTLA-4Ig, another phenotype-defining factor of Tregs' immunosuppressive
effects is ADO. In an animal model of ARDS, bronchial instillation of ADO reduces microvascular permeability
in the lungs. Therefore, we will include ADO in the formulation to generate muxTICA.
The experiments proposed are designed to advance an off-the-shelf immunosuppressant strategy as a logical
extension of the original specific aims in the context of an urgent medical need. Therefore, the studies in the
original and revision applications are conceptually and technologically synergistic and complementary.

## Key facts

- **NIH application ID:** 10144556
- **Project number:** 3R21AI139828-02S1
- **Recipient organization:** DUQUESNE UNIVERSITY
- **Principal Investigator:** Wilson S Meng
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $47,784
- **Award type:** 3
- **Project period:** 2020-07-02 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144556

## Citation

> US National Institutes of Health, RePORTER application 10144556, DEVELOPMENT OF A REGULATORY T CELL MIMETIC FOR TOLERANCE INDUCTION IN SKIN TRANSPLANTATION (3R21AI139828-02S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10144556. Licensed CC0.

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