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Front. Immunol. | doi: 10.3389/fimmu.2019.02724

18F-AzaFol for detection of folate receptor-β positive macrophages in experimental interstitial lung disease – a proof-of-concept study

  • 1Center for Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Switzerland
  • 2Center for Radiopharmaceutical Sciences, Paul Scherrer Institut, Switzerland
  • 3Department of Chemistry and Applied Biosciences, ETH Zurich, Switzerland
  • 4Institute for Diagnostic and Interventional Radiology, Zurich University Hospital, Switzerland
  • 5Institute of Pathology and Molecular Pathology, University Hospital Zurich, Switzerland
  • 6Division of Rheumatology and Immunology, Medical University of South Carolina, United States

Interstitial lung disease (ILD) is a common and severe complication in rheumatic diseases. Folate receptor-β is expressed on activated, but not resting macrophages which play a key role in dysregulated tissue repair including ILD. We therefore aimed to pre-clinically evaluate the potential of 18F-AzaFol-based PET/CT (positron emission computed tomography/computed tomography) for the specific detection of macrophage-driven pathophysiologic processes in experimental ILD.
The pulmonary expression of folate receptor-β was analysed in patients with different subtypes of ILD as well as in bleomycin (BLM)-treated mice and respective controls using immunohistochemistry. PET/CT was performed at days 3, 7, and 14 after BLM instillation using the 18F-based folate radiotracer 18F-AzaFol. The specific pulmonary accumulation of the radiotracer was assessed by ex vivo PET/CT scans and quantified by ex vivo biodistribution studies.
Folate receptor-β expression was 3- to 4-fold increased in patients with fibrotic ILD, including idiopathic pulmonary fibrosis and connective tissue disease-related ILD, and significantly correlated with the degree of lung remodelling. A similar increase in the expression of folate receptor-β was observed in experimental lung fibrosis, where it also correlated with disease extent.
In the mouse model of BLM-induced ILD, pulmonary accumulation of 18F-AzaFol reflected macrophage-related disease development with good correlation of folate receptor-β positivity with radiotracer uptake. In the ex vivo imaging and biodistribution studies, the maximum lung accumulation was observed at day 7 with a mean accumulation of 1.01 ± 0.30% injected activity/lung in BLM-treated versus control animals (0.31 ± 0.06% % injected activity/lung; p<0.01).
Our preclinical proof-of-concept study demonstrated the potential of 18F-AzaFol as a novel imaging tool for the visualisation of macrophage-driven fibrotic lung diseases.

Keywords: Interstitial lung disease (ILD), imaging biomarkers, Bleomycin-induced lung fibrosis, PET - Positron Emission Tomography, Macrophages, folate receptor-based imaging

Received: 14 Aug 2019; Accepted: 06 Nov 2019.

Copyright: © 2019 Schniering, Benešová, Brunner, Haller, Cohrs, Frauenfelder, Vrugt, Feghali-Bostwick, Schibli, Distler, Müller and Maurer. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Britta Maurer, Center for Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Zürich, 8091, Zürich, Switzerland,