Metz, Imke

[["dc.bibliographiccitation.firstpage","640"],["dc.bibliographiccitation.issue","5"],["dc.bibliographiccitation.journal","Brain Pathology"],["dc.bibliographiccitation.lastpage","657"],["dc.bibliographiccitation.volume","29"],["dc.contributor.author","Traub, Jan"],["dc.contributor.author","Traffehn, Sarah"],["dc.contributor.author","Ochs, Jasmin"],["dc.contributor.author","Häusser‐Kinzel, Silke"],["dc.contributor.author","Stephan, Schirin"],["dc.contributor.author","Scannevin, Robert"],["dc.contributor.author","Brück, Wolfgang"],["dc.contributor.author","Metz, Imke"],["dc.contributor.author","Weber, Martin S."],["dc.date.accessioned","2019-12-02T09:57:51Z"],["dc.date.accessioned","2021-10-27T13:21:40Z"],["dc.date.available","2019-12-02T09:57:51Z"],["dc.date.available","2021-10-27T13:21:40Z"],["dc.date.issued","2019"],["dc.description.abstract","n multiple sclerosis (MS), the effect of dimethyl fumarate (DMF) treatment is primarily attributed to its capacity to dampen pathogenic T cells. Here, we tested whether DMF also modulates B cells, which are newly recognized key players in MS, and to which extent DMF restricts ongoing loss of oligodendrocytes and axons in the central nervous system (CNS). Therefore, blood samples and brain tissue from DMF-treated MS patients were analyzed by flow cytometry or histopathological examination, respectively. Complementary mechanistic studies were conducted in inflammatory as well as non-inflammatory CNS demyelinating mouse models. In this study, DMF reduced the frequency of antigen-experienced and memory B cells and rendered remaining B cells less prone to activation and production of pro-inflammatory cytokines. Dissecting the functional consequences of these alterations, we found that DMF ameliorated a B cell-accentuated experimental autoimmune encephalomyelitis model by diminishing the capacity of B cells to act as antigen-presenting cells for T cells. In a non-inflammatory model of toxic demyelination, DMF limited oligodendrocyte apoptosis, promoted maturation of oligodendrocyte precursors and reduced axonal damage. In a CNS biopsy of a DMF-treated MS patient, we equivalently observed higher numbers of mature oligodendrocytes as well as a reduced extent of axonal damage when compared to a cohort of treatment-naïve patients. In conclusion, we showed that besides suppressing T cells, DMF dampens pathogenic B cell functions, which probably contributes to its clinical effectiveness in relapsing MS. DMF treatment may furthermore limit chronically ongoing CNS tissue damage, which may reduce long-term disability in MS apart from its relapse-reducing capacity."],["dc.identifier.doi","10.1111/bpa.12711"],["dc.identifier.pmid","30706542"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16772"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/92039"],["dc.language.iso","en"],["dc.notes.intern","Migrated from goescholar"],["dc.relation.eissn","1750-3639"],["dc.relation.issn","1750-3639"],["dc.relation.issn","1015-6305"],["dc.relation.orgunit","Universitätsmedizin Göttingen"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","Dimethyl fumarate impairs differentiated B cells and fosters central nervous system integrity in treatment of multiple sclerosis"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1"],["dc.bibliographiccitation.journal","Acta Neuropathologica"],["dc.bibliographiccitation.lastpage","14"],["dc.contributor.author","Hoepner, Robert"],["dc.contributor.author","Bagnoud, Maud"],["dc.contributor.author","Pistor, Maximilian"],["dc.contributor.author","Salmen, Anke"],["dc.contributor.author","Briner, Myriam"],["dc.contributor.author","Synn, Helen"],["dc.contributor.author","Schrewe, Lisa"],["dc.contributor.author","Guse, Kirsten"],["dc.contributor.author","Ahmadi, Farhad"],["dc.contributor.author","Demir, Seray"],["dc.contributor.author","Laverick, Louis"],["dc.contributor.author","Gresle, Melissa"],["dc.contributor.author","Worley, Paul"],["dc.contributor.author","Reichardt, Holger Michael"],["dc.contributor.author","Butzkueven, Helmut"],["dc.contributor.author","Gold, Ralf"],["dc.contributor.author","Metz, Imke"],["dc.contributor.author","Lühder, Fred"],["dc.contributor.author","Chan, Andrew"],["dc.date.accessioned","2019-07-09T11:51:33Z"],["dc.date.available","2019-07-09T11:51:33Z"],["dc.date.issued","2019"],["dc.description.abstract","The limited efficacy of glucocorticoids (GCs) during therapy of acute relapses in multiple sclerosis (MS) leads to long-term disability. We investigated the potential of vitamin D (VD) to enhance GC efficacy and the mechanisms underlying this VD/GC interaction. In vitro, GC receptor (GR) expression levels were quantified by ELISA and induction of T cell apoptosis served as a functional readout to assess synergistic 1,25(OH)2D3 (1,25D)/GC effects. Experimental autoimmune encephalomyelitis (MOG35-55 EAE) was induced in mice with T cell-specific GR or mTORc1 deficiency. 25(OH)D (25D) levels were determined in two independent cohorts of MS patients with stable disease or relapses either responsive or resistant to GC treatment (initial cohort: n = 110; validation cohort: n = 85). Gene expression of human CD8+ T cells was analyzed by microarray (n = 112) and correlated with 25D serum levels. In vitro, 1,25D upregulated GR protein levels, leading to increased GC-induced T cell apoptosis. 1,25D/GC combination therapy ameliorated clinical EAE course more efficiently than respective monotherapies, which was dependent on GR expression in T cells. In MS patients from two independent cohorts, 25D deficiency was associated with GC-resistant relapses. Mechanistic studies revealed that synergistic 1,25D/GC effects on apoptosis induction were mediated by the mTOR but not JNK pathway. In line, 1,25D inhibited mTORc1 activity in murine T cells, and low 25D levels in humans were associated with a reduced expression of mTORc1 inhibiting tuberous sclerosis complex 1 in CD8+ T cells. GR upregulation by 1,25D and 1,25D/GC synergism in vitro and therapeutic efficacy in vivo were abolished in animals with a T cell-specific mTORc1 deficiency. Specific inhibition of mTORc1 by everolimus increased the efficacy of GC in EAE. 1,25D augments GC-mediated effects in vitro and in vivo in a T cell-specific, GR-dependent manner via mTORc1 inhibition. These data may have implications for improvement of anti-inflammatory GC therapy."],["dc.identifier.doi","10.1007/s00401-019-02018-8"],["dc.identifier.pmid","31030237"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16149"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59968"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.issn","1432-0533"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","Vitamin D increases glucocorticoid efficacy via inhibition of mTORC1 in experimental models of multiple sclerosis"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]