Chemokine Receptor 2–targeted Molecular Imaging in Pulmonary Fibrosis

Steven L. Brody, Sean P. Gunsten, Hannah P. Luehmann, Debbie H. Sultan, Michelle Hoelscher, Gyu Seong Heo, Jiehong Pan, Jeffrey R. Koenitzer, Ethan C. Lee, Tao Huang, Cedric Mpoy, Shuchi Guo, Richard Laforest, Amber Salter, Tonya D. Russell, Adrian Shifren, Christophe Combadiere, Kory J. Lavine, Daniel Kreisel, Benjamin D. HumphreysBuck E. Rogers, David S. Gierada, Derek E. Byers, Robert J. Gropler, Delphine L. Chen, Jeffrey J. Atkinson, Yongjian Liu

Research output: Contribution to journalArticlepeer-review

Abstract

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive inflammatory lung disease without effective molecular markers of disease activity or treatment responses. Monocyte and interstitial macrophages that express the C-C motif CCR2 (chemokine receptor 2) are active in IPF and central to fibrosis. Objectives: To phenotype patients with IPF for potential targeted therapy, we developed 64Cu-DOTA-ECL1i, a radiotracer to noninvasively track CCR21 monocytes and macrophages using positron emission tomography (PET). Methods: CCR21 cells were investigated in mice with bleomycin- or radiation-induced fibrosis and in human subjects with IPF. The CCR21 cell populations were localized relative to fibrotic regions in lung tissue and characterized using immunolocalization, single-cell mass cytometry, and Ccr2 RNA in situ hybridization and then correlated with parallel quantitation of lung uptake by 64Cu-DOTA-ECL1i PET. Measurements and Main Results: Mouse models established that increased 64Cu-DOTA-ECL1i PET uptake in the lung correlates with CCR21 cell infiltration associated with fibrosis (n = 72). As therapeutic models, the inhibition of fibrosis by IL-1b blockade (n = 19) or antifibrotic pirfenidone (n = 18) reduced CCR21 macrophage accumulation and uptake of the radiotracer in mouse lungs. In lung tissues from patients with IPF, CCR21 cells concentrated in perifibrotic regions and correlated with radiotracer localization (n = 21). Human imaging revealed little lung uptake in healthy volunteers (n = 7), whereas subjects with IPF (n = 4) exhibited intensive signals in fibrotic zones. Conclusions: These findings support a role for imaging CCR21 cells within the fibrogenic niche in IPF to provide a molecular target for personalized therapy and monitoring.

Original languageEnglish (US)
Pages (from-to)78-89
Number of pages12
JournalAmerican journal of respiratory and critical care medicine
Volume203
Issue number1
DOIs
StatePublished - Jan 1 2021
Externally publishedYes

Keywords

  • CCR2
  • Macrophages
  • Monocytes
  • Positron emission tomography
  • Pulmonary fibrosis

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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