Abstract
BackgroundExperimental autoimmune encephalomyelitis (EAE) is an animal model that captures many of the hallmarks of human multiple sclerosis (MS), including blood–brain barrier (BBB) breakdown, inflammation, demyelination and axonal destruction. The standard clinical score measurement of disease severity and progression assesses functional changes in animal mobility; however, it does not offer information regarding the underlying pathophysiology of the disease in real time. The purpose of this study was to apply a novel optical imaging technique that offers the advantage of rapid imaging of relevant biomarkers in live animals.MethodsAdvances in non-invasive fluorescence molecular tomographic (FMT) imaging, in combination with a variety of biological imaging agents, offer a unique, sensitive and quantifiable approach to assessing disease biology in living animals. Using vascular (AngioSense 750EX) and protease-activatable cathepsin B (Cat B 680 FAST) near infrared (NIR) fluorescence imaging agents to detect BBB breakdown and inflammation, respectively, we quantified brain and spinal cord changes in mice with relapsing-remitting PLP139-151-induced EAE and in response to tolerogenic therapy.ResultsFMT imaging and analysis techniques were carefully characterized and non-invasive imaging results corroborated by both ex vivo tissue imaging and comparison to clinical score results and histopathological analysis of CNS tissue. FMT imaging showed clear differences between control and diseased mice, and immune tolerance induction by antigen-coupled PLGA nanoparticles effectively blocked both disease induction and accumulation of imaging agents in the brain and spinal cord.ConclusionsCat B 680 FAST and AngioSense 750EX offered the combination best able to detect disease in both the brain and spinal cord, as well as the downregulation of disease by antigen-specific tolerance. Non-invasive optical tomographic imaging thus offers a unique approach to monitoring neuroinflammatory disease and therapeutic intervention in living mice with EAE.
Highlights
Experimental autoimmune encephalomyelitis (EAE) is an animal model that captures many of the hallmarks of human multiple sclerosis (MS), including blood–brain barrier (BBB) breakdown, inflammation, demyelination and axonal destruction
Imaging CNS vascular leak in EAE with AngioSense 750EX To assess whether mouse EAE can be effectively imaged by fluorescence molecular tomographic (FMT), we used an near infrared (NIR) vascular imaging agent, AngioSense 750EX (AS750), to detect vascular leaks in the blood–brain barrier associated with CNS disease
Mice were injected with 4 nmol of AS750 when disease severity in half of the mice achieved a clinical score of 2–3, and imaging was performed 24 h later to allow optimal accumulation of the agent in BBB-compromised areas of the CNS
Summary
Experimental autoimmune encephalomyelitis (EAE) is an animal model that captures many of the hallmarks of human multiple sclerosis (MS), including blood–brain barrier (BBB) breakdown, inflammation, demyelination and axonal destruction. The experimental autoimmune encephalomyelitis (EAE) model of MS captures many of the hallmarks of the human disease [1,2]. EAE can be induced in specific strains of mice by immunization with CNS tissue homogenates, purified myelin proteins or peptides derived from these proteins, providing a valuable model for the assessment of the immune-related cellular and molecular contributors to disease induction or progression [3,4]. A variety of clinical imaging modalities have been applied to EAE studies, including positron emission tomography (PET), singlephoton emission computed tomography (SPECT) and magnetic resonance imaging (MRI). MRI imaging is expensive and can show a poor correlation between MRI findings and clinical symptoms [12], advances in targeted MRI contrast agents [13,14] are beginning to provide more useful biological and immunological information
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