CD80 Is Upregulated in a Mouse Model with Shear Stress-Induced Atherosclerosis and Allows for Evaluating CD80-Targeting PET Tracers
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A shear stress-induced atherosclerosis mouse model was characterized for its expression of inflammation markers with focus on CD80. With this model, we evaluated two positron emission tomography (PET) radiotracers targeting CD80 as well as 2-deoxy-2-[18F]fluoro-d-mannose ([18F]FDM) in comparison with 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG).
A flow constrictive cuff implanted around the common carotid artery in apolipoprotein E knockout mice resulted in plaque formation. CD80 expression levels and plaque histopathology were evaluated. Serial PET/X-ray computed tomography scans were performed to follow inflammation.
Plaque formation with increased levels of CD80 was observed. Histologically, plaques presented macrophage-rich and large necrotic areas covered by a thin fibrous cap. Of the CD80-specific tracers, one displayed an increased uptake in plaques by PET. Both [18F]FDG and [18F]FDM accumulated in atherosclerotic plaques.
This mouse model presented, similar to humans, an increased expression of CD80 which renders it suitable for non-invasively targeting CD80-positive immune cells and evaluating CD80-specific radiotracers.
Key wordsPositron emission tomography Atherosclerosis CD80 ApoE KO Shear stress Plaque inflammation [18F]FDG
Fluorescence-activated cell sorting
Positron emission tomography
Standardized uptake value
The authors thank Bruno Mancosu and Sabina Wunderlin for the technical support and helpful advice. We thank Dr. Michael Kuhlmann and Dirk Reinhardt from the European Institute for Molecular Imaging (EIMI, Münster, Germany) for introducing us to the shear stress-induced atherosclerosis mouse model and surgical training. We thank Dr. Cristina Müller (PSI, Villigen) for providing access to the Fuji ChemDri instrument and teaching sublingual blood collection. Ante Brekalo is acknowledged for the support in FDM synthesis. We appreciate the statistical advice by the statistical consultant of ETH. The authors acknowledge the support of the Scientific Center for Optical and Electron Microscopy (ScopeM) of the ETH Zurich. This work was financially supported by the Clinical Research Priority Program (CRPP) of the University of Zurich on Molecular Imaging (MINZ).
R.M. conceived of and designed the experiments; established and performed all animal experiments, ex vivo staining, ex vivo PET, FACS, and qPCR; analyzed the data; and wrote the manuscript. L.S. performed the qPCR experiments and ex vivo staining and analyzed the data. N.B. supervised and analyzed the immunohistochemistry experiments. L.M. established the FDM chemistry and radiolabeling of 18F-FDM and was involved in the discussion of results. C.K. established and conducted all animal surgeries and in vivo PET scans. A.C. performed the organic synthesis of the AC74 precursor and reference compounds and radiolabeling of [18F]AC74. E.R. and C.H. conducted and analyzed the FACS experiments. S.M.A. and R.S. were involved in the discussion of results and revision of the manuscript. S.D.K. contributed to the supervision and planning of the experiments and revised the manuscript. A.M.H. supervised the study, experimental planning, and data interpretation and contributed to and supervised the manuscript writing.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
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