# Mechanisms that Promote Chronic Lung Transplant Rejection

> **NIH NIH P01** · WASHINGTON UNIVERSITY · 2021 · $386,852

## Abstract

PROJECT SUMMARY/ABSTRACT
Lung recipients suffer from shorter life spans and higher rejection rates when compared to other solid organ
recipients. Bronchiolitis obliterans syndrome (BOS) is the most common cause of chronic lung transplant
rejection. Based on clinical outcome studies that have identified many known non-alloimmune mediators of
epithelial injury as risk factors for BOS, we have developed a new mouse orthotopic lung transplant model that
recapitulates this relationship. This innovation has allowed us to a identify a key airway epithelial cell progenitor,
the club cell, as vital for the maintenance of allograft tolerance and the prevention of obliterative bronchiolitis
(OB) - the major pathological indicator of BOS. We have also observed that OB is driven by graft-infiltrating
effector CD8+ T cells that inhibit club cell-mediated repair of airway epithelium. New data from our laboratory
suggests that follicular cytotoxic CD8+ T cells, a poorly defined CD8+ T cell subset with no reported role in solid
organ transplantation, may facilitate responses against pulmonary-self antigens. Our group has previously
reported that CCR2+ monocytes (CM) and neutrophil extracellular traps (NETs) play critical roles in both lung
transplant ischemia-reperfusion injury and the induction of lung allograft tolerance, but their role in the
maintenance of tolerance remains unclear. We have now uncovered evidence implicating graft-infiltrating CM
and NETs in OB pathogenesis. Here we propose to dissect the mechanisms by which CM (Aim 1), effector
CD8+ T cells (Aim 2) and NETs (Aim 3) promote OB pathogenesis. We will also examine how CM and NETs
shape effector CD8+ T cell responses that promote OB pathogenesis. Through these studies, we expect to
reveal targetable pathways that promote BOS.

## Key facts

- **NIH application ID:** 10197019
- **Project number:** 5P01AI116501-07
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Andrew Eric Gelman
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $386,852
- **Award type:** 5
- **Project period:** 2015-05-12 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197019

## Citation

> US National Institutes of Health, RePORTER application 10197019, Mechanisms that Promote Chronic Lung Transplant Rejection (5P01AI116501-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10197019. Licensed CC0.

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