# Endogenous memory T cell mediated rejection of high-risk cardiac allografts

> **NIH NIH F30** · CLEVELAND CLINIC LERNER COM-CWRU · 2024 · $53,974

## Abstract

ABSTRACT
Transplantation is the most effective treatment for end-stage organ diseases. Clinically, two important risk factors
for poor transplant outcomes are the pre-transplant presence of donor-reactive T cells in the recipient and the
length of graft cold ischemic storage (CIS) time prior to transplant. In kidney transplant patients, the pre-
transplant presence of circulating donor-reactive memory T cells is associated with an increased risk of acute
rejection episodes, delayed and decreased graft function and worse long-term graft survival. In unsensitized
recipients, donor-reactivity of memory T cells is due to heterologous (cross-reactive) immunity. However, the
mechanisms activating donor-reactive endogenous memory T cells within allografts to mediate acute graft injury
remain poorly understood. Prolonged CIS increases ischemia-reperfusion injury (IRI), which is characterized by
production of reactive oxygen species and proinflammatory cytokines that direct infiltration of recipient leukocytes
into the graft and cause activation of these cells within the graft. IRI also induces the graft to release damage
associated molecular patterns (DAMPs) from injured and dying cells that exacerbate inflammation and contribute
to worse outcomes in higher risk allografts. We previously showed that these two risk factors for poor transplant
outcomes are linked. The sustained high-inflammatory environment seen following transplant of cardiac
allografts subjected to prolonged CIS is necessary for sufficient activation of donor-reactive memory T cells to
mediate costimulatory blockade resistant acute rejection in unsensitized recipients. Multiple clinical transplant
studies have shown that one DAMP, cell-free DNA is elevated in the circulation during allograft injury,
representing a promising non-invasive biomarker for early detection of acute rejection. Additionally, recent work
from our collaborators has found new, pharmacologically targetable signaling partners required for activation of
innate immune sensors of cell free DNA, such as TLR9 which can recognize mitochondrial DNA (mtDNA). These
findings and our current preliminary data have led us to hypothesize that prolonged CIS and subsequent
increased IRI enhance the release of mtDNA, leading to greater TLR9 activation and downstream type I IFN
production, triggering a pro-inflammatory cycle that is sustained by endogenous donor-reactive memory T cell
mediated acute graft injury. This hypothesis will be tested in two specific aims using our vascularized mouse
heterotopic heart transplant model: first, we will test modulation of TLR9 signaling in vivo to assess impact on
donor-reactive memory T cell mediated acute graft injury; and second, we will test the mechanism(s) by which
type I interferon contributes to early post-transplant inflammation and activation of donor-reactive T cells to
mediate rejection. We anticipate that these studies will identify new targets for therapeutic strategies to improve
s...

## Key facts

- **NIH application ID:** 10891423
- **Project number:** 5F30AI174667-02
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Erik Harrison Koritzinsky
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,974
- **Award type:** 5
- **Project period:** 2023-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891423

## Citation

> US National Institutes of Health, RePORTER application 10891423, Endogenous memory T cell mediated rejection of high-risk cardiac allografts (5F30AI174667-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10891423. Licensed CC0.

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