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An obligatory role for club cells in preventing obliterative bronchiolitis in lung transplants
Zhiyi Liu, … , Steven L. Brody, Andrew E. Gelman
Zhiyi Liu, … , Steven L. Brody, Andrew E. Gelman
Published April 16, 2019
Citation Information: JCI Insight. 2019;4(9):e124732. https://doi.org/10.1172/jci.insight.124732.
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Research Article Immunology Transplantation

An obligatory role for club cells in preventing obliterative bronchiolitis in lung transplants

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Abstract

Obliterative bronchiolitis (OB) is a poorly understood airway disease characterized by the generation of fibrotic bronchiolar occlusions. In the lung transplant setting, OB is a pathological manifestation of bronchiolitis obliterans syndrome (BOS), which is a major impediment to long-term recipient survival. Club cells play a key role in bronchiolar epithelial repair, but whether they promote lung transplant tolerance through preventing OB remains unclear. We determined if OB occurs in mouse orthotopic lung transplants following conditional transgene-targeted club cell depletion. In syngeneic lung transplants club cell depletion leads to transient epithelial injury followed by rapid club cell–mediated repair. In contrast, allogeneic lung transplants develop severe OB lesions that are largely devoid of club cells despite immunosuppression treatment. Lung allograft club cell ablation also triggers the recognition of alloantigens, and pulmonary restricted self-antigens reported associated with BOS development. However, CD8+ T cell depletion restores club cell reparative responses and prevents OB. In addition, ex vivo analysis reveals a specific role for alloantigen-primed CD8+ T cells in inhibiting club cell proliferation and maintenance. Taken together, our results demonstrate a vital role for club cells in maintaining lung transplant tolerance and propose a model to identify the underlying mechanisms of OB.

Authors

Zhiyi Liu, Fuyi Liao, Davide Scozzi, Yuka Furuya, Kaitlyn N. Pugh, Ramsey Hachem, Delphine L. Chen, Marlene Cano, Jonathan M. Green, Alexander S. Krupnick, Daniel Kreisel, Anne Karina T. Perl, Howard J. Huang, Steven L. Brody, Andrew E. Gelman

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Figure 1

Lung allograft recipients are unable to repair their bronchiolar epithelium following club cell depletion.

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Lung allograft recipients are unable to repair their bronchiolar epithel...
(A) A mouse OLT model that generates OB in 16 days. B6 recipients of 3T FVB left lungs treated with CD40L Abs (POD 0) and CTLA4Ig (POD 2) to establish tolerance were fed doxycycline by food and water (DOX) from POD 7 to 9.5 and analyzed for graft inflammation on POD 16. 3T FVB and 3T B6 (B) donor lungs and (C) transplants stained with CCSP and Ac-tubulin Abs on POD 7, 11, and 16. Scale bars: 50 μm. Data shown are a representative result from at least 3 independent experiments.

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