# Post-Transplant Inflammatory Response

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2021 · $483,002

## Abstract

Abstract
Acute allograft rejection is a T cell mediated immune response that continues to undermine the success of
transplantation to treat end-stage organ disease. Two factors contributing to acute and chronic allograft injury
and graft loss are ischemia-reperfusion injury and heterologous immunity by endogenous memory T cells with
reactivity to graft alloantigens. Reperfusion of ischemic tissues is an inherent component of transplantation and
quickly induces an acute inflammatory response that directs the infiltration and activation of many types of
leukocytes in the tissue. Clinically, the presence of donor-reactive memory T cells in the peripheral blood of
kidney transplant patients prior to transplant is associated with increased delayed graft function and poorer graft
survival. However, the mechanisms activating donor-reactive endogenous memory T cells within allografts to
mediate graft injury remain poorly understood. Studies performed during the last funding period indicated that
endogenous memory CD8 T cells rapidly infiltrate cardiac allografts and are activated by graft allogeneic class
I MHC molecules to proliferate and produce IFN- and other factors mediating graft tissue injury. The infiltration
and activities of endogenous memory CD8 T cells are markedly increased in allografts subjected to longer
duration of cold ischemic storage (CIS) prior to transplant that promotes costimulatory blockade resistant
memory CD8 T cell rejection of the allografts. These and our preliminary results have led us to propose the
hypothesis that the increased inflammation generated following reperfusion of allografts subjected to
prolonged, but not to minimal, CIS initiates a cycle of interdependent innate immune interactions with
pre-existing donor-reactive memory CD4 and CD8 T cells required to sustain activation of the memory
CD8 T cells to mediate acute graft injury and CTLA-4Ig-resistant rejection. The hypothesis will be tested
in two specific aims: first, we will test the mechanisms promoting activation of the donor-reactive endogenous
memory CD8 T cells within the highly ischemic allografts; and, second, we will test the role of TLR9 signaling
in sustaining the inflammatory cycle leading to activation of the memory CD8 T cells to reject the allografts and
the ability of new strategies to inhibit TLR9-mediated inflammation to improve outcomes of these higher risk
allografts. Experiments in this renewal application will connect ischemia-reperfusion injury with pre-existing
donor-reactive memory T cell activation in grafts and provide novel insights into mechanisms underlying an
important and poorly understood clinical problem. We anticipate these studies will identify new targets for
therapeutic strategies to inhibit innate immune enhancement of pre-existing donor-reactive memory T cells in
grafts and acute T cell mediated graft injury and improve graft outcomes.

## Key facts

- **NIH application ID:** 10075875
- **Project number:** 5R01AI040459-22
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Robert L Fairchild
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $483,002
- **Award type:** 5
- **Project period:** 1997-04-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10075875

## Citation

> US National Institutes of Health, RePORTER application 10075875, Post-Transplant Inflammatory Response (5R01AI040459-22). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10075875. Licensed CC0.

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