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The development of a new model of progressive multiple sclerosis
Author(s): ,
J. Roodselaar
Affiliations:
Pharmacology, University of Oxford, Oxford, United Kingdom
,
Y. Zhou
Affiliations:
Pharmacology, University of Oxford, Oxford, United Kingdom
,
D.C. Anthony
Affiliations:
Pharmacology, University of Oxford, Oxford, United Kingdom
Experimental neuropathology
Affiliations:
Pharmacology, University of Oxford, Oxford, United Kingdom
ECTRIMS Online Library. Roodselaar J. Oct 12, 2018; 228902
Jay Roodselaar
Jay Roodselaar
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Abstract: P1061

Type: Poster Sessions

Abstract Category: Pathology and pathogenesis of MS - Experimental models

Multiple sclerosis (MS) is a chronic, autoimmune, demyelinating disease of the central nervous system. Relapse remitting MS (RRMS) is characterised by active lesions with demyelination and oligodendrocyte loss, infiltration of T cells and monocytes, and disruption of the blood-brain barrier (BBB). This appears to be different in progressive MS (PMS), where lesions are less likely to be actively demyelinating, the BBB is often intact, and the proportion of B cells and plasma cells in the brain increases. B cells are thought to play a role in antigen presentation and other antibody-independent roles in MS. Moreover, tertiary lymphoid structures (TLS), enriched in B cells, have been found to be present in two thirds of patients with PMS and are associated with more severe pathology. After the successful completion of phase III clinical trials for anti-CD20 antibodies in RRMS and in primary PMS, a disease modifying therapy (DMT) for secondary PMS (SPMS) is still lacking. To better understand how anti-CD20 therapy impacts on B cell populations in the CNS in PMS, there is now a need for the development of relevant models of MS with ectopic lymphoid structures.
Focal brain lesions with TLS were induced in humanised CD20 mice following the stereotaxic injection of heat-killed Mycobacterium Tuberculosis into the piriform cortex after immunisation with MOG-peptide in complete Freund adjuvant. Animals were treated with an anti-CD20 antibody or control in a rescue manner. The effect of the treatment the TLS, glial activation, myelination and neuronal death was examined by histology.
TLS formed in the mice in close proximity to the lesion core and continue to enlarge over time. At day 60, MRI revealed no Gadolinium enhancement in these animals, but the follicular structures were still present and enlarging with associated neuronal loss in the underlying cortex. Treatment with anti-CD20 antibodies decreased the number of B and T lymphocytes in the brain and in the TLS, and reduced the extent of glial activation.
SPMS with TLS can be modelled in rodents, with lesions that continue to evolve over time behind an intact BBB. Anti-CD20 antibody treatment reduced the size of the TLS significantly as well as the general number of T and B lymphocytes in the brain. Moreover, anti-CD20 treatment reduced the extent of brain inflammation in general, demonstrating the importance of B cells in MS pathogenesis and the potential of using anti-CD20 as a DMT for progressive MS.
Disclosure: Nothing to disclose

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