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dc.contributor.advisor Nessler, Stefan Dr.
dc.contributor.author Lagumersindez Denis, Nielsen
dc.date.accessioned 2015-11-20T13:14:49Z
dc.date.available 2016-11-09T23:50:04Z
dc.date.issued 2015-11-20
dc.identifier.uri http://hdl.handle.net/11858/00-1735-0000-0028-8638-F
dc.language.iso eng de
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc 610
dc.title Immunopathogenesis of cortical demyelination in Multiple Sclerosis de
dc.type doctoralThesis de
dc.contributor.referee Brück, Wolfgang Prof. Dr.
dc.date.examination 2015-11-09
dc.description.abstracteng Cortical demyelination is a key pathological feature of multiple sclerosis (MS) and clinically linked to cognitive deficits and disability progression. Extensive band-like subpial demyelination is even a specific feature of the disease. However, the immunological mechanisms driving cortical demyelination have not yet been defined due to a lack of cortical pathology in the classical experimental models of MS. To elucidate the immunopathogenesis of cortical demyelination, we developed a novel mouse model with subpial and perivascular cortical MS-like lesions. We demonstrate that in addition to a pathogenic anti-myelin antibody response, perivascular cortical demyelination is primarily dependent on activated encephalitogenic T cells, natural killer (NK) cells and CCR2+ inflammatory monocytes. In contrast, subpial cortical demyelination occurs independently of activated T cells, but requires specific antibodies and a fully functional complement cascade. To translate the results obtained into a treatment option for MS, we evaluated the therapeutic efficacy of a humanized mouse anti-human CCR2 antibody, which efficiently depletes CCR2+ monocytes in marmosets with experimental autoimmune encephalomyelitis (EAE). Depleting inflammatory monocytes was well tolerated and significantly reduced cortical demyelination in marmoset monkeys with EAE. Our findings thus delineate a differential involvement of immunological effector mechanisms in perivascular and subpial cortical lesion formation, shed light on the exquisite vulnerability of subpial cortical tissue in multiple sclerosis and translate into a preclinical treatment approach for cortical demyelination. de
dc.contributor.coReferee Reichardt, Holger Prof. Dr.
dc.subject.eng cortical demyelination de
dc.subject.eng multiple sclerosis de
dc.subject.eng EAE de
dc.subject.eng stereotactic injection de
dc.subject.eng transgenic mouse model de
dc.subject.eng marmoset de
dc.identifier.urn urn:nbn:de:gbv:7-11858/00-1735-0000-0028-8638-F-3
dc.affiliation.institute Medizinische Fakultät
dc.subject.gokfull Medizin (PPN619874732) de
dc.description.embargoed 2016-11-09
dc.identifier.ppn 84048691X

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