Molecular imaging of the TGF-β activating integrin αvβ6 detects chronic lung allograft dysfunction

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Abstract

TGF-β-activating integrins promote solid-organ fibrosis, suggesting their potential as disease markers. Chronic lung allograft dysfunction (CLAD), a progressive fibrotic complication that limits lung transplant survival, is driven by intragraft TGF-β activation. However, TGF-β-activating integrin expression patterns remain undefined in lung transplants. Single-cell RNA sequencing and proteomic analysis of tissue specimens from a mouse CLAD model and human explanted lungs with CLAD revealed high levels of the TGF-β-activating integrin αvβ6, primarily localized to fibrosis-associated Keratin 8+ alveolar transitional epithelial cells, which were greatly reduced in tolerant lungs. Molecular imaging with a newly optimized positron emission tomography radiotracer specific for αvβ6, [64Cu]Cu-DOTA-A20-K16R, showed significantly higher uptake in CLAD than in tolerant transplants. [64Cu]Cu-DOTA-A20-K16R activity was also reduced by experimental treatments that lowered αvβ6 expression and inhibited CLAD severity. Finally, [64Cu]Cu-DOTA-A20-K16R autoradiographic analysis of human explanted lungs with CLAD showed elevated activity that correlated with increased αvβ6 expression. Collectively, these findings illustrate the potential utility of αvβ6 molecular imaging for detecting CLAD pathogenesis.

Authors

Marlene Cano, Chandra S. Bathula, Fuyi Liao, Cristian Wieczorek Villas Boas, Yan Tao, Zhiyi Liu, Ricky Ebenezer, Victoria Davis, Allison Cannady, Dequan Zhou, Shunning Liang, Hanqiu Zhao, Derek E. Byers, Alexander S. Krupnick, Daniel Kreisel, Susan M. Lin, Allen Duong, Tereza Martinu, Zhiyu Dai, Buck E. Rogers, Andrew E. Gelman