| 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.identifier.uri | http://dx.doi.org/10.53846/goediss-5375 | |
| 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 | |