title: In vivo nanoparticle imaging of innate immune cells can serve as a marker of disease severity in a model of multiple sclerosis.
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.
authors: German Cancer Consortium, Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.|Department of Neuroradiology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors: Klara
authors: K
authors: Kirschbaum
authors: German Cancer Consortium, Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors: Jana K
authors: JK
authors: Sonner
authors: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115.|Division of Neuroradiology, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115.
authors: Matthias W
authors: MW
authors: Zeller
authors: German Cancer Consortium, Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors: Katrin
authors: K
authors: Deumelandt
authors: Schaller Research Group, University of Heidelberg and DKFZ, 69120 Heidelberg, Germany.|Molecular Mechanisms of Tumor Invasion, DKFZ, 69120 Heidelberg, Germany.
authors: Julia
authors: J
authors: Bode
authors: Schaller Research Group, University of Heidelberg and DKFZ, 69120 Heidelberg, Germany.|Molecular Mechanisms of Tumor Invasion, DKFZ, 69120 Heidelberg, Germany.
authors: Rakesh
authors: R
authors: Sharma
authors: Schaller Research Group, University of Heidelberg and DKFZ, 69120 Heidelberg, Germany.|Molecular Mechanisms of Tumor Invasion, DKFZ, 69120 Heidelberg, Germany.
authors: Thomas
authors: T
authors: Krüwel
authors: Department of Neuroradiology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors: Manuel
authors: M
authors: Fischer
authors: Department of Neuroradiology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors: Angelika
authors: A
authors: Hoffmann
authors: Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, 69120 Heidelberg, Germany.|Molecular Medicine Partnership Unit, University Hospital Heidelberg, 69120 Heidelberg, Germany.|Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto, 4050-313 Porto, Portugal.
authors: Milene
authors: M
authors: Costa da Silva
authors: Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, 69120 Heidelberg, Germany.|Molecular Medicine Partnership Unit, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors: Martina U
authors: MU
authors: Muckenthaler
authors: Department of Neurology and National Center for Tumor Diseases (NCT), University Hospital Heidelberg, 69120 Heidelberg, Germany.|German Cancer Consortium, Clinical Cooperation Unit Neurooncology, DKFZ, 69120 Heidelberg, Germany.
authors: Wolfgang
authors: W
authors: Wick
authors: Schaller Research Group, University of Heidelberg and DKFZ, 69120 Heidelberg, Germany.|Molecular Mechanisms of Tumor Invasion, DKFZ, 69120 Heidelberg, Germany.
authors: Björn
authors: B
authors: Tews
authors: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115.|Division of Neuroradiology, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115.
authors: John W
authors: JW
authors: Chen
authors: Department of Neuroradiology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors: Sabine
authors: S
authors: Heiland
authors: Department of Neuroradiology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors: Martin
authors: M
authors: Bendszus
authors: German Cancer Consortium, Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.|Department of Neurology and National Center for Tumor Diseases (NCT), University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors: Michael
authors: M
authors: Platten
authors: 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.|Department of Neuroradiology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors: Michael O
authors: MO
authors: Breckwoldt
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000000981:diagnostic imaging* / Q000276:immunology; D005260:Female; D007113:Immunity, Innate; D008264:Macrophages / Q000276:immunology; D008279:Magnetic Resonance Imaging; D058185:Magnetite Nanoparticles / Q000008:administration & dosage*; D051379:Mice; D017628:Microglia / Q000276:immunology; D009103:Multiple Sclerosis / Q000000981:diagnostic imaging* / Q000276:immunology; D010587:Phagocytosis; D012720:Severity of Illness Index
chemical_list: D058185:Magnetite Nanoparticles
keywords: EAE; MRI; USPIO; multiple sclerosis; nanoparticle imaging