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Proc Natl Acad Sci U S A. 2016 Nov 15;113(46):13227-13232. Epub 2016 Oct 31.

In vivo nanoparticle imaging of innate immune cells can serve as a marker of disease severity in a model of multiple sclerosis.

Author information

1
German Cancer Consortium, Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
2
Department of Neuroradiology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
3
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115.
4
Division of Neuroradiology, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115.
5
Schaller Research Group, University of Heidelberg and DKFZ, 69120 Heidelberg, Germany.
6
Molecular Mechanisms of Tumor Invasion, DKFZ, 69120 Heidelberg, Germany.
7
Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, 69120 Heidelberg, Germany.
8
Molecular Medicine Partnership Unit, University Hospital Heidelberg, 69120 Heidelberg, Germany.
9
Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto, 4050-313 Porto, Portugal.
10
Department of Neurology and National Center for Tumor Diseases (NCT), University Hospital Heidelberg, 69120 Heidelberg, Germany.
11
German Cancer Consortium, Clinical Cooperation Unit Neurooncology, DKFZ, 69120 Heidelberg, Germany.
12
German Cancer Consortium, Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; michael.breckwoldt@med.uni-heidelberg.de.

Abstract

Innate immune cells play a key role in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Current clinical imaging is restricted to visualizing secondary effects of inflammation, such as gliosis and blood-brain barrier disruption. Advanced molecular imaging, such as iron oxide nanoparticle imaging, can allow direct imaging of cellular and molecular activity, but the exact cell types that phagocytose nanoparticles in vivo and how phagocytic activity relates to disease severity is not well understood. In this study we used MRI to map inflammatory infiltrates using high-field MRI and fluorescently labeled cross-linked iron oxide nanoparticles for cell tracking. We confirmed nanoparticle uptake and MR detectability ex vivo. Using in vivo MRI, we identified extensive nanoparticle signal in the cerebellar white matter and circumscribed cortical gray matter lesions that developed during the disease course (4.6-fold increase of nanoparticle accumulation in EAE compared with healthy controls, P < 0.001). Nanoparticles showed good cellular specificity for innate immune cells in vivo, labeling activated microglia, infiltrating macrophages, and neutrophils, whereas there was only sparse uptake by adaptive immune cells. Importantly, nanoparticle signal correlated better with clinical disease than conventional gadolinium (Gd) imaging (r, 0.83 for nanoparticles vs. 0.71 for Gd-imaging, P < 0.001). We validated our approach using the Food and Drug Administration-approved iron oxide nanoparticle ferumoxytol. Our results show that noninvasive molecular imaging of innate immune responses can serve as an imaging biomarker of disease activity in autoimmune-mediated neuroinflammation with potential clinical applications in a wide range of inflammatory diseases.

KEYWORDS:

EAE; MRI; USPIO; multiple sclerosis; nanoparticle imaging

PMID:
27799546
PMCID:
PMC5135308
DOI:
10.1073/pnas.1609397113
[Indexed for MEDLINE]
Free PMC Article

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