Antigen-specific immunotherapy is an immunomodulatory strategy for autoimmune diseases, such as type 1 diabetes, in which patients are treated with autoantigens to promote immune tolerance, stop autoimmune β-cell destruction and prevent... more
Antigen-specific immunotherapy is an immunomodulatory strategy for autoimmune diseases, such as type 1 diabetes, in which patients are treated with autoantigens to promote immune tolerance, stop autoimmune β-cell destruction and prevent permanent dependence on exogenous insulin. In this study, human proinsulin peptide C19-A3 (known for its positive safety profile) was conjugated to ultrasmall gold nanoparticles (GNPs), an attractive drug delivery platform due to the potential anti-inflammatory properties of gold. We hypothesised that microneedle intradermal delivery of C19-A3 GNP may improve peptide pharmacokinetics and induce tolerogenic immunomodulation and proceeded to evaluate its safety and feasibility in a first-in-human trial. Allowing for the limitation of the small number of participants, intradermal administration of C19-A3 GNP appears safe and well tolerated in participants with type 1 diabetes. The associated prolonged skin retention of C19-A3 GNP after intradermal admin...
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S. Serres, S. Mardiguian, M. A. McAteer, R. P. Choudhury, S. J. Campbell, P. Smith, F. Saunders, N. R. Sibson, and D. C. Anthony Gray Institute for Radiation Oncology and Biology, Oxford, Oxon, United Kingdom, Department of Pharmacology,... more
S. Serres, S. Mardiguian, M. A. McAteer, R. P. Choudhury, S. J. Campbell, P. Smith, F. Saunders, N. R. Sibson, and D. C. Anthony Gray Institute for Radiation Oncology and Biology, Oxford, Oxon, United Kingdom, Department of Pharmacology, University of Oxford, Department of Cardiovascular Medicine, Department of Cardiovascular Medicine, University of Oxford, Department of Pharmacology, university of Oxford, Department of Pharmacology, UCB, Slough, Department of Antibody Biology, UCB, Slough, Gray Institute for Radiation Oncology and Biology, University of Oxford
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ABSTRACTGold nanoparticles (GNPs) have been used in the development of novel therapies as a way of delivery of both stimulatory and tolerogenic peptide cargoes. Here we report that intradermal injection of GNPs loaded with the proinsulin... more
ABSTRACTGold nanoparticles (GNPs) have been used in the development of novel therapies as a way of delivery of both stimulatory and tolerogenic peptide cargoes. Here we report that intradermal injection of GNPs loaded with the proinsulin peptide C19-A3, in patients with type 1 diabetes, results in recruitment and retention of immune cells in the skin. These include large numbers of clonally expanded T-cells sharing the same paired T-cell receptors (TCRs) with activated phenotypes, half of which, when the TCRs were re-expressed in a cell-based system, were confirmed to be specific for either GNP or proinsulin. All the identified gold-specific clones were CD8+, whilst proinsulin-specific clones were both CD8+and CD4+. Proinsulin-specific CD8+clones had a distinctive cytotoxic phenotype with overexpression of granulysin (GNLY) and KIR receptors. Clonally expanded antigen-specific T cells remainedin situfor months to years, with a spectrum of tissue resident memory and effector memory p...
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Purpose: To evaluate the feasibility of high‐resolution magnetic resonance imaging (MRI) of trabecular bone of the wrist at 3 Tesla (3T) in vivo and to assess the potential benefit of the increased resolution for clinical assessment of... more
Purpose: To evaluate the feasibility of high‐resolution magnetic resonance imaging (MRI) of trabecular bone of the wrist at 3 Tesla (3T) in vivo and to assess the potential benefit of the increased resolution for clinical assessment of structural changes in spongy bone. Material and Methods: High‐resolution MRI of the wrist was performed with a whole‐body 3T MR scanner using a dedicated circularly polarized transmit–receive wrist‐coil. Two 3D‐FISP sequences with a spatial resolution of 300×300×300 µm3 in a measuring time of TA = 7:51 min, and 200×200×200 µm3 in TA = 9:33 min were applied. Seven young healthy volunteers and three elderly subjects with suspected osteoporosis were examined. The signal‐to‐noise ratio (SNR) in the optimized setup at 3T was compared to measurements at 1.5T. Results: The images at 3T allow microscopic analysis of the bone structure at an isotropic spatial resolution of 200 µm in examination times of <10 min. Differences in the structure of the spongy bo...
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Nicholas J. Alp, Martina A. McAteer, Jeffrey Khoo, Robin P. Choudhury and Keith M. Atherosclerosis in ApoE-Knockout Mice GTP-Cyclohydrolase I Overexpression Reduces Endothelial Dysfunction and Increased Endothelial Tetrahydrobiopterin... more
Nicholas J. Alp, Martina A. McAteer, Jeffrey Khoo, Robin P. Choudhury and Keith M. Atherosclerosis in ApoE-Knockout Mice GTP-Cyclohydrolase I Overexpression Reduces Endothelial Dysfunction and Increased Endothelial Tetrahydrobiopterin Synthesis by Targeted Transgenic Print ISSN: 1079-5642. Online ISSN: 1524-4636 Copyright © 2004 American Heart Association, Inc. All rights reserved. Greenville Avenue, Dallas, TX 75231 is published by the American Heart Association, 7272 Arteriosclerosis, Thrombosis, and Vascular Biology doi: 10.1161/01.ATV.0000115637.48689.77 2004;24:445-450; originally published online January 5, 2004; Arterioscler Thromb Vasc Biol. http://atvb.ahajournals.org/content/24/3/445 World Wide Web at: The online version of this article, along with updated information and services, is located on the
SummaryThe National Cancer Imaging Translational Accelerator (NCITA) is creating a UK national coordinated infrastructure for accelerated translation of imaging biomarkers for clinical use. Through the development of standardised... more
SummaryThe National Cancer Imaging Translational Accelerator (NCITA) is creating a UK national coordinated infrastructure for accelerated translation of imaging biomarkers for clinical use. Through the development of standardised protocols, data integration tools and ongoing training programmes, NCITA provides a unique scalable infrastructure for imaging biomarker qualification using multicentre clinical studies.
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Introduction: Targeted microparticles of iron oxide (MPIO) can detect endothelial inflammation in advanced mouse atherosclerosis by ex vivo magnetic resonance imaging (MRI). However, the sensitivit...
Research Interests: Medicine and Circulation
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The Golden Syrian hamster (Mesocricetus auratus) has been shown to be a useful model of both human lipoprotein metabolism and the development of atherosclerosis. We report the effects of dietary lipids on the progression and regression of... more
The Golden Syrian hamster (Mesocricetus auratus) has been shown to be a useful model of both human lipoprotein metabolism and the development of atherosclerosis. We report the effects of dietary lipids on the progression and regression of atherosclerosis in this model. In the first study, hamsters fed on coconut oil (150 g/kg diet) and cholesterol (30 g/kg diet) developed lipid-rich lesions in the ascending aorta (0·28 (sd 0·14) mm2) and aortic arch (0·01 (sd 0·01) mm2) after 4 weeks that continued to progress over the next 8 weeks (0·75 (sd 0·41) mm2 and 0·12 (sd 0·11) mm2 for the ascending aorta and aortic arch respectively). Removal of cholesterol from the diet halted this progression. Furthermore, in animals fed on olive oil in the absence of added cholesterol, plasma LDL-cholesterol concentrations were lower (P < 0·05) and the extent of atherosclerotic lesions was reduced (P < 0·001 for both regions of the aorta) compared with animals fed on coconut oil (with no added cho...
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Abstract 12255: Noninvasive Molecular Imaging of Differential Endothelial Adhesion Molecule Expression in Early Atherosclerosis Correlates With Plaque Macrophage Content in Apo E Knockout Mice Martina A McAteer; Kulveer Mankia; Rachel... more
Abstract 12255: Noninvasive Molecular Imaging of Differential Endothelial Adhesion Molecule Expression in Early Atherosclerosis Correlates With Plaque Macrophage Content in Apo E Knockout Mice Martina A McAteer; Kulveer Mankia; Rachel Hagen; Lee-Anne A Stork; Jurgen E Schneider; Robin P Choudhury Univ of Oxford, Oxford, United Kingdom Introduction: Targeted microparticles of iron oxide (MPIO) can detect endothelial inflammation in advanced mouse atherosclerosis by ex vivo magnetic resonance imaging (MRI). However, the sensitivity of MPIO for non-invasive detection of early endothelial activation has not been established. Hypothesis: MPIO targeting both P-selectin and VCAM-1 can detect endothelial activation in early mouse atherosclerosis by in vivo MRI. Methods: MPIO (1 µm) were conjugated to P-selectin and VCAM-1 monoclonal antibodies (50:50) (PV-MPIO) or IgG-1 control (IgG-MPIO). Female apoE –/– mice fed standard chow diet for 8, 14, 20 and 30 weeks underwent in vivo MRI (9.4 Tesl...
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We have compared lipoprotein metabolism in, and susceptibility to atherosclerosis of, two strains of male Golden Syrian hamster, the Bio F1B hybrid and the dominant spot normal inbred (DSNI) strain. When fed a normal low-fat diet... more
We have compared lipoprotein metabolism in, and susceptibility to atherosclerosis of, two strains of male Golden Syrian hamster, the Bio F1B hybrid and the dominant spot normal inbred (DSNI) strain. When fed a normal low-fat diet containing approximately 40 g fat and 0·3 g cholestero/g, triacylglycerol-rich lipoprotein (chylomicron+VLDL) and HDL-cholesterol were significantly higher (P<0·001) in Bio F1B hamsters than DSNI hamsters. When this diet was supplemented with 150 g coconut oil and either 0·5 or 5·0 g cholestero/g, significant differences were seen in response. In particular, the high-cholesterol diet produced significantly greater increases in plasma cholesterol and triacylglycerol in the Bio F1B compared with the DSNI animals (P=0·002 andP<0·001 for cholesterol and triacylglycerol, respectively). This was particularly dramatic in non-fasting animals, suggesting an accumulation of chylomicrons. In a second experiment, animals were fed 150 g coconut oi/g and 5·0 g chol...
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Metastasis to the brain is a leading cause of cancer mortality. The current diagnostic method of gadolinium-enhanced MRI is sensitive only to larger tumors, when therapeutic options are limited. Earlier detection of brain metastases is... more
Metastasis to the brain is a leading cause of cancer mortality. The current diagnostic method of gadolinium-enhanced MRI is sensitive only to larger tumors, when therapeutic options are limited. Earlier detection of brain metastases is critical for improved treatment. We have developed a targeted MRI contrast agent based on microparticles of iron oxide that enables imaging of endothelial vascular cell adhesion molecule-1 (VCAM-1). Our objectives here were to determine whether VCAM-1 is up-regulated on vessels associated with brain metastases, and if so, whether VCAM-1–targeted MRI enables early detection of these tumors. Early up-regulation of cerebrovascular VCAM-1 expression was evident on tumor-associated vessels in two separate murine models of brain metastasis. Metastases were detectable in vivo using VCAM-1–targeted MRI 5 d after induction (<1,000 cells). At clinical imaging resolutions, this finding is likely to translate to detection at tumor volumes two to three orders o...
Research Interests: Brain Imaging, Cancer, Magnetic Resonance Imaging, MRI, Immunohistochemistry, and 15 moreMetastasis, Medicine, Multidisciplinary, Humans, Mice, Animals, In Vivo, Gadolinium, Disease Progression, Sensitivity and Specificity, Brain Neoplasms, Academy of Sciences and Letters, Brain Metastasis, vascular cell adhesion molecule 1, and VCAM
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Research Interests: Biophysics, Chemistry, Flow Cytometry, Fluorescence Microscopy, Atherosclerosis, and 15 moreImmunohistochemistry, Humans, Animals, Male, Article, Clinical Sciences, Endothelial cell, Biological markers, Ligands, Ferric Compounds, Arterioles, Cardiovascular medicine and haematology, Human Umbilical Vein Endothelial Cells, Coronary Vessels, and Inflammation Mediators
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Objective— Endothelial cell activation is an important mediator of monocyte recruitment to sites of vascular inflammation. We hypothesized that high-affinity dual-ligand microparticles of iron oxide (MPIO), targeted to P-selectin and... more
Objective— Endothelial cell activation is an important mediator of monocyte recruitment to sites of vascular inflammation. We hypothesized that high-affinity dual-ligand microparticles of iron oxide (MPIO), targeted to P-selectin and vascular cell adhesion molecule-1 (PV-MPIO), would identify activated endothelial cells during atherosclerosis progression. Methods and Results— In vivo magnetic resonance imaging in apolipoprotein E-deficient mice showed rapid binding of PV-MPIO to the aortic root, which was maximal 30 minutes post-MPIO injection and maintained at 60 minutes. Minimal binding was observed for control IgG-MPIO. Intensely low magnetic resonance signal areas, corresponding to PV-MPIO binding, were detected early (14 weeks), during foam cell formation. Contrast effects increased at 20 weeks during fibrofatty lesion development ( P <0.05), but reduced by 30 weeks ( P <0.01). Across all lesion severities, magnetic resonance imaging contrast effects correlated with lesio...
Research Interests: Flow Cytometry, Biology, Atherosclerosis, Inflammation, Immunohistochemistry, and 15 moreMacrophages, Antibodies, Humans, Female, Animals, Clinical Sciences, In Vivo, Biomimetic materials, Disease Progression, Aorta, Ligands, Ferric Compounds, Leukocytes, Contrast Media, and Cardiovascular medicine and haematology
Research Interests: Pathology, Physiology, Multiple sclerosis, Magnetic Resonance Imaging, Immunohistochemistry, and 15 moreMedicine, Brain, Humans, Mice, Female, Animals, Medical Physiology, Disease Progression, ENDOTHELIUM, Experimental Autoimmune Encephalomyelitis, Ferric Compounds, Contrast Media, Translational Medical Research, Biochemistry and cell biology, and vascular cell adhesion molecule 1
Research Interests: Inflammation and Medicine
Introduction Ischaemia/reperfusion injury (IRI) is an important cause of tissue damage in vascular syndromes of the heart, brain and kidney. Sensitive tools to image ischaemic injury non-invasively are lacking. We hypothesised that... more
Introduction Ischaemia/reperfusion injury (IRI) is an important cause of tissue damage in vascular syndromes of the heart, brain and kidney. Sensitive tools to image ischaemic injury non-invasively are lacking. We hypothesised that antibody-conjugated microparticles of iron oxide (MPIO) targeting vascular cell adhesion molecule 1 (VCAM-1) would enable molecular magnetic resonance imaging (MRI) of endothelial activation in a mouse model of renal IRI. Methods and Results MPIO (1.0 μm) were conjugated to monoclonal antibody against vascular cell adhesion molecule 1 (VCAM–MPIO). In male C57BL/6 mice (n = 10) the left renal pedicle was cross-clamped for 30 minutes to induce IRI. Following 12 h reperfusion, mice were anaesthetised with isofluorane and administered intravenously with VCAM–MPIO (n = 5) or negative control IgG–MPIO (n = 3). In-vivo MRI (9.4T) was performed for 90 minutes. VCAM–MPIO binding produced low signal areas in the clamped kidney, with little retention in the co...
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Molecular imaging offers great potential for noninvasive visualization and quantitation of the cellular and molecular components involved in atherosclerotic plaque stability. In this chapter, we review emerging molecular imaging... more
Molecular imaging offers great potential for noninvasive visualization and quantitation of the cellular and molecular components involved in atherosclerotic plaque stability. In this chapter, we review emerging molecular imaging modalities and approaches for quantitative, noninvasive detection of early biological processes in atherogenesis, including vascular endothelial permeability, endothelial adhesion molecule up-regulation, and macrophage accumulation, with special emphasis on mouse models. We also highlight a number of targeted imaging nanomaterials for assessment of advanced atherosclerotic plaques, including extracellular matrix degradation, proteolytic enzyme activity, and activated platelets using mouse models of atherosclerosis. The potential for clinical translation of molecular imaging nanomaterials for assessment of atherosclerotic plaque biology, together with multimodal approaches is also discussed.