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Title: Modelling progressive multiple sclerosis for new treatment strategies
Author: Roodselaar, Jay
ISNI:       0000 0004 8507 1704
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2019
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Multiple sclerosis (MS) is an autoimmune, demyelinating, degenerative disease of the central nervous system. Secondary progressive (SP) MS differs from relapse-remitting (RR) MS in clinical symptoms and histopathology. As disease progresses, the proportion of B cells and plasma cells increases in the brain. Moreover, meningeal tertiary lymphoid structures (TLS) are present in a large proportion of SPMS patients and are associated with more severe pathology. Treatment is available for suppressing relapses in RRMS, but no disease modifying therapy (DMT) is available for the ongoing disease worsening in SPMS. This is, in part, due to a lack of preclinical models for SPMS. There is a need for rodent models of SPMS to investigate disease mechanisms and treatment options. This thesis describes the development of two new rodent models of SPMS, characterised by glial activation, lymphocyte infiltration, demyelination, and neuronal death behind a closed blood-brain barrier (BBB). Focal MS-like lesions were induced by first immunising mice with MOG and CFA intradermally, followed by an intracranial injection with heat-killed mycobacterium tuberculosis in either the striatum or the piriform cortex. Mice were treated with anti-LINGO-1 or anti-CD20 antibodies 4 weeks after initiation of the lesion. Treatment effects on the different aspects of the focal lesions were evaluated by immunohistochemistry. MS-like lesions formed in the brains independent of injection site. However, TLS were only formed in mice with lesions in the piriform cortex. Both types of lesions continued to grow over time. Anti-LINGO-1 therapy promoted oligodendrocyte survival and reduced glial activation in the brains of these mice. Treatment with anti-CD20 decreased the extent of glial activation, significantly decreased the number of B and T lymphocytes, and reduced the size of the TLS. SPMS with and without TLS can be modelled in rodents, with lesions that continue to evolve over time behind an intact BBB. Two different treatments were shown to be effective in this model, demonstrating the potential of using anti-LINGO-1 or anti-CD20 as a DMT for SPMS.
Supervisor: Anthony, Daniel Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available