# Inflammatory Cellular Mechanisms for Establishing and Maintaining Lung Allograft Tolerance

> **NIH NIH P01** · WASHINGTON UNIVERSITY · 2020 · $498,077

## Abstract

PROJECT SUMMARY/ABSTRACT
Studies utilizing the murine model of lung transplantation have helped advance our understanding
of lung allograft-specific immunoregulation. Unlike other solid organs, the lung relies on pro-
inflammatory feedback loops for establishing and maintaining graft acceptance. We have
described that CD8+ T cells, long considered deleterious to solid organ allograft survival, play a
critical role in lung allograft tolerance. During the last funding period we have uncovered that
lung-resident eosinophils, also considered a detrimental cell population for graft health, shape
CD8+ T cell fate to prevent their effector differentiation. We have also described that such
eosinophil-CD8+ T cell feedback loops play a crucial role in maintaining graft survival in vivo. We
have further demonstrated the translational potential of this discovery and ameliorated graft
rejection by altering eosinophil migration into the lung through intra-tracheal administration of
chemokines. Such data provides proof of principle that mechanistic studies utilizing murine
models offer the possibility for the development of lung-specific protocols for immunosuppression
and tolerance induction. In project #2 we propose to decipher multiple aspects of lung allograft-
specific proinflammatory loops in tolerance induction and maintenance. In aim #1 we plan to
explore the interactions of IFN-γ and IL1-β in lung allograft acceptance and in aim #2 we will focus
on antigen specificity in tolerance induction as well as mechanism/s mediating T cell receptor
instability. In aim #3 we will focus on the role of PD-L1 in maintenance of tolerance. In addition
we will explore the potential for bi-specific antibody-mediated induction of tolerance through
forced interaction of eosinophils and T cells. The studies proposed here would lay the foundation
for translational large animal and human work in lung allograft management in an effort to improve
survival.

## Key facts

- **NIH application ID:** 10024445
- **Project number:** 2P01AI116501-06
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** ALEXANDER S. KRUPNICK
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $498,077
- **Award type:** 2
- **Project period:** 2015-05-12 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10024445

## Citation

> US National Institutes of Health, RePORTER application 10024445, Inflammatory Cellular Mechanisms for Establishing and Maintaining Lung Allograft Tolerance (2P01AI116501-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10024445. Licensed CC0.

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