Reactivation of a CNS Lesion by a Systemic Inflammatory Response

Lead Research Organisation: University of Oxford
Department Name: Physiology Anatomy and Genetics

Abstract

Lay Summary: Multiple Sclerosis is a disease of the brain and spinal cord, with devastating effects on human health. The major consequence of the disease process is to impair the ability of nerves to transmit electrical impulses, which can cause various forms of disability depending on the site within the brain that is affected. Most individuals with multiple sclerosis experience periods of disability (relapses) followed by periods of recovery. However, we still do not understand what causes relapse. It is likely that there are many causes of relapse, although infections (e.g. urinary tract infections) have been suggested to be an important contributing factor. Magnetic resonance imaging (MRI) provides images of the brain in which changes can be seen when disease or damage is present. Consequently, MRI provides an important way in which to diagnose and monitor multiple sclerosis. Under this research proposal, we plan to use MRI to study the relationship between infections and relapse in a clinically-relevant model of MS. We will also investigate whether current and novel treatments for multiple sclerosis may be able to prevent or reduce relapse caused by infections in our properly controlled experimental systems. By investigating one of the possible causes of relapse in multiple sclerosis, we aim to significantly improve our ability to treat individuals with multiple sclerosis.

We have established web sites both in Oxford (www.bioch.ox.ac.uk/mrs) and in Southampton (www.soton.ac.uk/~da3) to promote the activities of our MRC Co-operative and to disseminate our findings. If the application is successful, the lay summary will be placed on the web sites, which will be updated as the milestones are reached.

Technical Summary

The majority of individuals with multiple sclerosis (MS) display the relapsing-remitting form of disease, but the causes of relapse remain unclear. Both viral and bacterial infections have been implicated in the pathogenesis of MS, but the precise relationship between infection and relapse has been hard to define in clinical studies. Magnetic resonance imaging (MRI) is now widely used in the diagnosis and monitoring of MS, but there is often a mismatch between clinical symptoms and MRI indices of disease activity. This confound has made evaluation of the role of infection in MS relapse particularly problematic. One possible explanation for the mismatch is that current MRI methods fail to identify all of the active lesions in the brain; it is rare for post-mortem tissue to become available that can be compared directly to MRI images for analysis. This issue may be readily addressed, in appropriate clinically relevant animal models. Using such models, we have discovered that there can be evolving neuropathology in CNS lesions that are undetectable by the conventional MRI methods used in MS, such as contrast enhancement. We have also discovered that increases in cerebral blood volume (CBV) precede conventional measures of lesion load, and may, therefore, represent a further marker of lesion development. Our pilot studies have shown that a systemic challenge with bacterial endotoxin, which mimics aspects of a bacterial infection, can reactivate an MRI-invisible CNS lesion; once again, an increase in CBV was the earliest indication that a lesion was present. Under this proposal, we will investigate the relationship between systemic infection and reactivation of a CNS lesion. We will use MRI to follow the effects of a systemic inflammatory response on a quiescent immune-mediated demyelinating lesion in the rat brain (a focal MOG model), which shares many of the pathological hallmarks of an MS lesion. We will use challenges that mimic aspects of both bacterial and viral infections to investigate the relationship between the severity of systemic challenges and lesion reactivation. In addition, we will correlate the MRI signal changes with the underlying neuropathology by immunohistochemical and molecular biology techniques and by the use of novel MRI contrast agents. We will use established and novel therapeutics to determine whether we can manipulate the reactivation process. This multidisciplinary proposal will have implications for the management and treatment of MS patients; we expect the results of these studies to form the foundation of a translational clinical investigation.

Publications

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Anthony DC (2014) Anti-CD20 inhibits T cell-mediated pathology and microgliosis in the rat brain. in Annals of clinical and translational neurology

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Serres S (2009) Systemic inflammatory response reactivates immune-mediated lesions in rat brain. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Serres S (2013) Magnetic resonance imaging reveals therapeutic effects of interferon-beta on cytokine-induced reactivation of rat model of multiple sclerosis. in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

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Serres S (2011) VCAM-1-targeted magnetic resonance imaging reveals subclinical disease in a mouse model of multiple sclerosis. in FASEB journal : official publication of the Federation of American Societies for Experimental Biology

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Van Kasteren SI (2009) Glyconanoparticles allow pre-symptomatic in vivo imaging of brain disease. in Proceedings of the National Academy of Sciences of the United States of America

 
Description NC3Rs/MRC CRACK IT Review Panel A
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description CRUK Programme Grant
Amount £3,200,000 (GBP)
Funding ID C28462/A10158 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2007 
End 03/2013
 
Description MRC Capacity Building Studentship
Amount £66,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2009 
End 09/2011
 
Description Novartis collaboration 
Organisation Novartis
Country Global 
Sector Private 
PI Contribution On the basis of our work in the rat EAE models under this grant, we have established a collaboration with Novartis to investigate the action of one of their novel therapeutics using our new targeted contrast agent approach together with conventional imaging methods.
Impact Dickens AM (Dickens, A. M.), Anthony DC (Anthony, D. C.), Claridge TDW (Claridge, T. D. W.), Mardiguian S (Mardiguian, S.), Cavay A (Cavay, A.), Davis BG (Davis, B. G.), Griffin JL (Griffin, J. L.), Campbell SJ (Campbell, S. J.), Palace J (Palace, J.), Sibson NR (Sibson, N. R.) Source: MULTIPLE SCLEROSIS Volume: 15 Issue: 9 Pages: S275-S275 Supplement: Suppl. S Published: SEP 2009 ISSN: 1352-4585
Start Year 2008
 
Description Roche collaboration 
Organisation F. Hoffmann-La Roche AG
Country Global 
Sector Private 
PI Contribution On the basis of our work in the rat EAE models under this grant, we have established a collaboration with Roche to investigate the action of one of their novel therapeutics using our new targeted contrast agent approach together with conventional imaging methods.
Impact No outputs yet.
Start Year 2010
 
Description MSc and DTC Lectures 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Regular lectures on brain imaging in cancer and neurosciences to Doctoral Training Course and M.Sc. students, which sparked questions and discussion as well as interest in entering research within this field of research. Outcome is often one or more students joining the group for either M.Sc. or D.Phil. projects.

Development of collaborations and numerous examples of interest in applying our VCAM-targeted technology in different patients groups from paediatrics to head injury.
Year(s) Of Engagement Activity 2009,2010,2011,2012,2013,2014,2015,2016