# Ocular Immune Regulation by Mesenchymal Stem Cells

> **NIH NIH R01** · SCHEPENS EYE RESEARCH INSTITUTE · 2021 · $477,725

## Abstract

This is a competitive renewal application to further characterize the immunoregulatory function of
mesenchymal stem cells (MSCs) in ocular inflammation. Renowned for promoting tissue regeneration and
immune quiescence, studies have demonstrated the therapeutic potential of MSCs in human disease.
Nevertheless, fundamental questions remain unanswered regarding their immunomodulatory mechanisms.
This proposal employs a well-characterized transplant model of the murine cornea to systematically
investigate how MSCs directly interact with T cells to suppress alloimmunity.
 Over recent years the work of several laboratories, including our own, has made substantial
progress in understanding how MSCs regulate ocular inflammation. With respect to corneal transplantation,
we and others have shown that exogenous administration of MSCs suppresses alloimmunity and promotes
graft survival. Reports from our lab provide evidence that MSCs: (i) specifically home to the ocular surface
following corneal transplantation, where they act to (ii) limit antigen-presenting cell (APC) maturation, and
(iii) decrease graft-destroying IFNγ + T helper-1 (Th1) cell responses. Moreover, our preliminary data and
reports from other groups indicate that administration of MSCs following transplantation induces Foxp3+
regulatory T cells (Tregs). Despite these observations, the exact mechanisms by which MSCs suppress
Th1 generation and induce Tregs are not known. Our preliminary investigations indicate that, in addition to
indirect modulation via APCs, MSCs exert a direct immunomodulatory effect on alloreactive T cells.
 We define 3 specific aims to answer the following questions: Aim 1: What are the mechanisms by
which MSCs inhibit generation of alloreactive Th1 cells? Aim 2: What are the mechanisms by which MSCs
inhibit effector function of alloreactive Th1 cells? And finally Aim 3: How do MSCs promote the generation
of tolerance-inducing Tregs? Our preliminary data implicate specific soluble and surface-bound
immunoregulatory molecules. Based on these data, we propose 3 hypotheses: (1) MSCs negatively
regulate early T cell activation via the surface-bound molecule ALCAM, resulting in decreased generation of
Th1 cells; (2) MSC-secreted IL11 suppresses Th1 function by antagonizing IFNγ and Tbet expression; and
(3) MSCs skew the differentiation of naïve T cells toward Foxp3+ Tregs via CD80/CTLA-4 interaction. The
principal objective of this project is to define the molecular mechanisms by which MSCs directly interact
with T cells to regulate alloimmunity. Given the considerable expense of delivering MSC-based cell
therapies, identifying the factors that mediate the immunoregulatory activity of MSCs is a research priority. It
is anticipated that completion of these entirely novel aims will elucidate as-yet-unknown mechanisms by
which MSCs regulate T cell responses, and may conceivably provide a framework for the development of
new therapeutic approaches in transplantation and other T c...

## Key facts

- **NIH application ID:** 10126850
- **Project number:** 5R01EY024602-07
- **Recipient organization:** SCHEPENS EYE RESEARCH INSTITUTE
- **Principal Investigator:** Sunil K Chauhan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $477,725
- **Award type:** 5
- **Project period:** 2015-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126850

## Citation

> US National Institutes of Health, RePORTER application 10126850, Ocular Immune Regulation by Mesenchymal Stem Cells (5R01EY024602-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10126850. Licensed CC0.

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