# Mechanisms that Promote Chronic Lung Transplant Rejection

> **NIH NIH P01** · WASHINGTON UNIVERSITY · 2024 · $373,015

## 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:** 10869914
- **Project number:** 5P01AI116501-10
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Andrew Eric Gelman
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $373,015
- **Award type:** 5
- **Project period:** 2015-05-12 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10869914

## Citation

> US National Institutes of Health, RePORTER application 10869914, Mechanisms that Promote Chronic Lung Transplant Rejection (5P01AI116501-10). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10869914. Licensed CC0.

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