# Immune Mechanisms in Ocular Graft versus Host Disease

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $410,000

## Abstract

Abstract
Allogeneic hematopoietic stem cell transplantation (aHSCT) has become the standard of care for treatment of
several life-threatening hematologic malignancies, immunodeficiency and genetic diseases. Unfortunately, as
the survival rate of these patients is improved, the quality of life is negatively impacted by Graft vs Host Disease
(GVHD). GVHD is a complex, multi-organ disorder arising from immunological attack by donor allo-reactive T
cells that results in damage to the GI tract, liver, skin and the eye. Ocular GVHD (oGVHD) occurs in >60% of
patients with GVHD and can threaten vision due to lacrimal gland and conjunctival damage leading to dry eye,
keratopathy and corneal perforation. Despite the high frequency of eye involvement in GVHD patients, little is
known regarding the underlying immune mechanisms responsible for oGVHD that lead to keratoconjunctivitis
sicca. Unfortunately, the ophthalmic care of these patients is restricted to palliative therapies and anti-
inflammatory drugs with limited mechanisms of action and efficacy. Our recent exciting findings using nanostring
analysis, support the notion that selected genes including cytokines, antigen presenting / MHC, T cell, and TNF
superfamily (TNFRSF) pathways are differentially regulated and involved in oGVHD affecting the conjunctiva
and lacrimal gland (Conj+LaGL). In this application, we continue to use pre-clinical models to understand why
the eye is a target tissue in GVHD and propose to develop new translational targeted immunotherapies to locally
prevent and treat oGVHD. Experiments here will investigate CD4 and CD8 Teff mediated damage to Conj+LaGL
(Aim 1). We will utilize our TCR transgenic (Tg) and newly developed double reporter (B6-nur77GFPFoxP3RFP)
mice to understand local activation of CD4 and CD8 Teff & Tregs. Using scRNAseq and mass cytometry imaging,
studies will provide insights into local T cells receiving alloantigen stimulation. Next, we will interrogate for the
first time, hematopoietic and non-hematopoietic antigen presenting cell (APC) pathways in oGVHD (Aim 2). We
will apply in vivo models combining TCR Tg donors with hematopoietic chimeras to enable precise interrogation
of direct and indirect antigen presentation pathways in the Conj+LaGL damage. These studies will drive
development of new strategies using biological reagents and epigenetic regulation for prevention and treatment
of aHSCT that can be translated to patients (Aim 3). Notably, our 2-receptor pathway strategy using a novel
fusion protein (TL1A-Ig) targeting TNFRSF25 and IL-2, which targets CD25 locally expands ocular Tregs.
Because bromodomain proteins have a central role in regulating transcription of inflammatory genes, we propose
to use inhibitors of these proteins (BETi), applied as a local ocular formulation to suppress cytokines by infiltrating
and parenchymal Conj+LaGL cell populations. Furthermore, we will generate a new oGVHD treatment approach
by combining our local 2-pathway Treg ...

## Key facts

- **NIH application ID:** 10122444
- **Project number:** 2R01EY024484-06
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Robert Benjamin Levy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $410,000
- **Award type:** 2
- **Project period:** 2014-05-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10122444

## Citation

> US National Institutes of Health, RePORTER application 10122444, Immune Mechanisms in Ocular Graft versus Host Disease (2R01EY024484-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10122444. Licensed CC0.

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