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In vivo visualization of macrophage infiltration and activity in inflammation using magnetic resonance imaging

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Abstract Because macrophages play a key role on host defense, visualization of the migration of these cells is of high relevance for both diagnostic purposes and the evaluation of therapeutic interventions. The present article addresses the use of iron oxide and gadolinium‐based particles for the noninvasive in vivo detection of macrophage infiltration into inflamed areas by magnetic resonance imaging (MRI). A general introduction on the functions and general characteristics of macrophages is followed by a discussion of some of the agents and acquisition schemes currently used to track the cells in vivo. Attention is then devoted to preclinical and clinical applications in the following disease areas: atherosclerosis and myocardial infarction, stroke, multiple sclerosis, rheumatoid arthritis, and kidney transplantation Copyright © 2009 John Wiley & Sons, Inc. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging

(a, b) Injection of USPIO caused spotted susceptibility effects of aortic wall in a heritable hyperlipidemic rabbit (arrows). (c, d) Histological analysis with modified Prussian blue staining shows superficial distribution of iron particles in the aortic vessel wall of the same animal (arrows; c, black bar represents 200 µm; magnification 25×; d, black bar represents 50 µm; magnification 100×). (e) Aorta of a non‐ hyperlipidemic, control rabbit without signal inhomogeneities in MRA, and (f) regular endothelial layer in histological section (black bar represents 200 µm; magnification 25×). Black triangle demarks the intimal and medial layer. FLASH MRA datasets were acquired at day 5 after USPIO injection. (Reprinted, with permission, from Ref. 78. Copyright 2006 Wiley Periodicals, Inc.).

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(a) Gradient‐echo images of a Fisher kidney transplanted into a Lewis rat, acquired at several time points with respect to transplantation. The recipient received SPIO 4 weeks prior to each measurement. Images were acquired without respiratory gating. On the right side, histology of Perl's Prussian blue reaction at week 32 demonstrating iron‐loaded macrophages in the kidney cortex. (b) Cortical MRI signal intensity (means ± sem) in grafts from vehicle‐treated recipients, from recipients treated with Sandimmun Neoral (1.5 mg/kg/day p.o. for 10 days) and from recipients treated with Neoral (1.5 mg/kg/day p.o. for 10 days) followed by Certican (1.25 mg/kg/day) for the remainder of the study. (c) A significant negative correlation (r = − 0.86, P < 0.0001) was found at week 32 between the iron content determined histologically and the MRI signal intensity. (d) The creatinine in the blood and the urine for the groups of recipients remained unchanged during the experimental time. See Refs 181, 182 for more details. (Modified, with permission, from Ref. 181. Copyright 2003 Wiley Periodicals, Inc.).

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(a) Coronal sections extracted from 3D images of the right knee of a placebo‐treated rat, acquired at different time points after mBSA injection into the same knee. SPIO had been administered 24 h before each measurement. The arrows highlight the signal attenuation in areas corresponding to synovial fluid effusion. (b) Coronal slice through the knee of a vehicle‐treated rat, 16 days after antigen administration. Berlin‐blue‐Giemsa‐stained histological images from the same knee. Arrows indicate a massive presence of iron‐loaded macrophages. (c) Course of MRI signal intensities (mean ± sem, N = 5 for each group of knees) relative to prechallenge values. Control knees refer to contralateral, vehicle‐treated knees, from the same rats that had received antigen on the ipsilateral joints. The levels of significance, *** P < 0.001, and # 0.01 < P < 0.05, ## 0.001 < P < 0.01, correspond to ANOVA comparisons carried out for antigen‐challenged knees from placebo‐ and dexamethasone‐treated animals, respectively. (d) Macrophage numbers (mean ± sem, N = 5) determined histologically on day 16 after challenge, in knees from untreated and dexamethasone‐treated rats. The level of significance refers to a t‐test comparison between both groups of animals. (Modified, with permission, from Ref. 147. Copyright 2003 Wiley Periodicals, Inc.).

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MRI examinations of two MS patients. For patient 1 (upper row), clear signal changes (enhancement on T1‐weighted, attenuation on T2*‐weighted MRI) were seen on an MS plaque. A mismatch of contrast agents uptake was seen in patient (lower row). While T1‐weighted images showed a large MS lesion that was not enhanced by Gd (arrowheads), the same acquisition performed 24 h after USPIO demonstrated an uptake of the agent at the periphery of the lesion (arrow). According to histological observations,136, 137 the number of macrophages at the center of acute MS lesions is usually minor. These observations raise the question whether macrophage tracking using USPIO could be a stronger predictor for MS development than imaging of increased BBB permeability using Gd‐DOTA. See Dousset et al.117 for details. (Reprinted, with permission, from Ref. 117 Copyright 2006 American Society of Neuroradiology.).

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Coronal T2*‐weighted MR images of the rat brain, 6 days after photothrombosis, with (a–c) and without (d–f) intravenous application of USPIO 24 h earlier. Representative sections through the most rostral (a, d), central (b, e), and caudal (c, f) levels of the lesion. (Reprinted, with permission, from Ref. 103. Copyright 2006 Wiley Periodicals, Inc.).

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In a rat EAE model, BBB leakage and cellular infiltration as monitored by Gd‐DTPA and USPIO contrast imaging. (a) Examples of T1‐weighted gradient‐echo difference images, showing the relative increase of the signal intensity after a bolus of 0.5 mM Gd‐DTPA (8 min in circulation) at different stages of EAE. Compared with an EAE animal at day 9 postimmunization, signal intensities start to increase in the cerebellum and brain stem from day 11 due to the leakage of the BBB. This leakage is even more pronounced at day 14. Eventually, the BBB integrity is restored at day 17. (b) T2‐weighted images of animals from different brain areas that were acquired 24 h after an intravenous bolus of 600 µmol Fe/kg USPIO. Note that the iron oxide starts to accumulate in the brain (as observed by a reduction of the T2‐weighted signal intensities) from day 11 after immunization. Massive USPIO accumulation was observed at the peak of the disease (day 14), whereas in the recovery phase (day 17), only few USPIOs were present in the CNS. (c) Clinical scores of EAE animals in time. Time course of clinical scores (bar) and body weight (line) in acute EAE of Lewis rats. Lewis rats were immunized with myelin basic protein emulsified in complete Freund's adjuvant at day Zero. Neurological symptoms were scored daily. Data represent mean ± sem; *P < 0.05. (Reprinted, with permission, from Ref. 129. Copyright 2004 Oxford University Press.).

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USPIO‐enhanced MRI of human brain infarction. Images of a 54‐year‐old man with infarction of the left middle cerebral artery territory showing the differential development of USPIO‐related signal changes over time. Compared with the (a) nonenhanced T1‐weighted image 5 days after stroke, T1‐weighted images (b) 24 and (c) 48 h after USPIO infusion show increasing hyperintense signal enhancement in the periphery of the infarcted parenchyma. (d) Nonenhanced T2*‐weighted images display hyperintense demarcation of the infarcted territory. T2*‐weighted images (e) 24 and (f) 48 h after USPIO infusion show a signal change from hyperintense to hypointense attributable to USPIO perfusion. T2* signal changes are mainly vessel‐associated, and can also be observed in the nonischemic hemisphere, and decrease over time (e, f). (Reprinted, with permission, from Ref. 114. Copyright 2004 Oxford University Press.).

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