# Immunogenomic analysis of donor lung injury and its impact on clinical outcomes after lung transplantation

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $721,966

## Abstract

The severity of lung injury that develops within the first several days after lung transplantation (LT) is a key
indicator of which LT recipients are at greatest risk of death or early development of chronic lung allograft
dysfunction. The fact that 30% of lungs deemed suitable for LT rapidly develop severe lung injury suggests that
there may be unrecognized subclinical injury already present in donor lungs that renders the lung allograft
susceptible to further injury at the time of LT. A critical unmet need is improved ability to detect and interpret
the consequences of subclinical donor lung injury that may drive poor clinical outcomes after LT. In this Katz
R01 proposal, an accomplished physician scientist will develop a new area of research investigating how
subclinical donor lung injury triggers a cascade of events that ultimately results in CLAD. Recent studies have
identified donor-derived cell-free DNA (cfDNA) as a biomarker of lung allograft injury, with increased cfDNA
detected prior to clinical recognition of acute rejection. However, it is unknown which specific cells and injury
mechanisms cause cfDNA release from the donor lung. cfDNA can also mechanistically exacerbate lung
inflammation. In models of non-LT lung injury, cfDNA detection in bronchoalveolar lavage or plasma activates
the stimulator of interferon genes (STING). STING then promotes ongoing dysregulated inflammation by
activating inflammatory pathways previously implicated in lung injury after LT, including NF-B, NLRP3, and
MKLK. In this Katz R01 proposal, an ESI physician scientist with clinical expertise in LT and scientific expertise
in animal models of ARDS proposes an integrated approach to define mechanisms of donor lung injury that
drive cfDNA release and poor outcomes after LT. Using single-cell genomics and CyTOF-based immune cell
profiling of serial samples from human donor lungs coupled with a new multi-hit murine model of subclinical
donor lung injury, we will determine the specific cellular and molecular mechanisms through which donor lung
injury affects early allograft dysfunction. We hypothesize that subclinical donor lung injury drives severe
allograft injury through release of donor-derived cfDNA into the allograft airspace, triggering a feed-forward
cycle of inflammation and ongoing cellular injury that results in poor clinical outcomes. The Specific Aims are:
(1) to test whether subclinical donor lung injury is associated with release of donor-derived cfDNA and poor
clinical outcomes in humans, using single-cell RNA sequencing and mass cytometry on donor lung biopsies
collected before and after LT and (2) to use a novel animal model of sequential subclinical lung injury prior to
ischemia reperfusion to determine how subclinical donor lung injury releases cfDNA to prime the donor lung to
develop excessive STING-dependent inflammation after ischemia-reperfusion injury. Together, the
combination of longitudinal human observational data and mechanistic mur...

## Key facts

- **NIH application ID:** 10877722
- **Project number:** 5R01HL160551-03
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Ciara M Shaver
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $721,966
- **Award type:** 5
- **Project period:** 2022-07-10 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877722

## Citation

> US National Institutes of Health, RePORTER application 10877722, Immunogenomic analysis of donor lung injury and its impact on clinical outcomes after lung transplantation (5R01HL160551-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10877722. Licensed CC0.

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