# Mechanisms of Sensitization in High Risk Corneal Grafts

> **NIH NIH R01** · SCHEPENS EYE RESEARCH INSTITUTE · 2024 · $671,244

## Abstract

This is a competitive renewal application to continue our work deciphering the molecular and cellular facets
of host immunity in high-risk corneal grafts, performed in inflamed host beds and distinguished by their
rapid rejection. Over the past 4 funded cycles, this project has led to over 100 scientific articles spanning
important areas of transplant immunity, including characterization of corneal antigen-presenting cell (APC)
populations and the mechanisms of their trafficking, regulation of hemangiogenesis and lymphangiogenesis,
mechanisms of T cell activation and homing, and the function of regulatory T cells (Treg) in promoting
immune quiescence and allotolerance. In the last 4 years, we have made significant progress, showing how
the microenvironment of a graft can regulate Treg phenotype: in the physiologic state, which is largely
maintained in the low-risk graft setting, Foxp3hi Treg express an array of membrane-associated inhibitory
factors (CTLA-4, PD-L1) and secreted anti-inflammatory cytokines (IL-10, TGFβ) that promote immune
tolerance and graft cytoprotection. This homeostasis is lost in the high-risk setting, leading to Treg
dysfunction and potential generation of a subset of Treg (`ex-Treg') that express pro-inflammatory cytokines
that cause tissue damage. In the current proposal, we aim to better understand the cross-regulation of APC
and Treg in different graft settings. Our overarching hypothesis is that the high-risk graft is characterized
by an ocular microenvironment that abrogates the capacity of Treg to suppress graft site APC maturation
(Aim 1), while these mature APC will in turn promote Treg dysfunction in the draining lymph node, the
critical site of host T cell sensitization and expansion (Aim 2). We then aim to exploit functional host Treg by
administering them locally to high-risk host beds to assess their anti-angiogenic functions (Aim 3). Our aims
are novel, addressing important gaps in our knowledge: Aim 1, investigating the differential capacity of
Treg derived from the ocular surface of HR vs. LR graft recipients in regulating APC maturation is the first
study in the field of transplantation evaluating regulation of APCs by Tregs at the graft site. Aim 2 will
address a major gap in our knowledge about how APC secretory function can influence Treg phenotype and
function. Aim 3 includes the first studies characterizing the mechanisms by which Treg exert anti-angiogenic
function in transplantation, a novel and potentially feasible therapeutic strategy in the HR transplant setting.
Our study design relies on the core expertise and extensive experience of our lab studying the
immunology of corneal transplantation. The overall health relevance of this research is that corneal
grafting is the number one form of transplantation performed in the US. While most high-risk transplants get
rejected, there has been no significant change in their management for 60+ years. The long-term objective
of our project is to develop n...

## Key facts

- **NIH application ID:** 10893024
- **Project number:** 5R01EY012963-25
- **Recipient organization:** SCHEPENS EYE RESEARCH INSTITUTE
- **Principal Investigator:** Reza Dana
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $671,244
- **Award type:** 5
- **Project period:** 2000-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10893024

## Citation

> US National Institutes of Health, RePORTER application 10893024, Mechanisms of Sensitization in High Risk Corneal Grafts (5R01EY012963-25). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10893024. Licensed CC0.

---

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