Lühder, Fred

[["dc.bibliographiccitation.artnumber","1319"],["dc.bibliographiccitation.firstpage","1"],["dc.bibliographiccitation.journal","Frontiers in Immunology"],["dc.bibliographiccitation.lastpage","13"],["dc.bibliographiccitation.volume","8"],["dc.contributor.author","Montes-Cobos, Elena"],["dc.contributor.author","Schweingruber, Nils"],["dc.contributor.author","Li, Xiao"],["dc.contributor.author","Fischer, Henrike J."],["dc.contributor.author","Reichardt, Holger M."],["dc.contributor.author","Lühder, Fred"],["dc.date.accessioned","2019-07-09T11:44:30Z"],["dc.date.available","2019-07-09T11:44:30Z"],["dc.date.issued","2017"],["dc.description.abstract","Myeloid cells play an important role in the pathogenesis of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Monocytes, macrophages, and microglia can adopt two distinct phenotypes, with M1-polarized cells being more related to inflammation and autoimmunity while M2-polarized cells contribute to tissue repair and anti-inflammatory processes. Here, we show that deletion of the mineralocorticoid receptor (MR) in bone marrow-derived macrophages and peritoneal macrophages caused their polarization toward the M2 phenotype with its distinct gene expression, altered phagocytic and migratory properties, and dampened NO production. After induction of EAE, mice that are selectively devoid of the MR in their myeloid cells (MRlysM mice) showed diminished clinical symptoms and ameliorated histological hallmarks of neuroinflammation. T cells in peripheral lymphoid organs of these mice produced less pro-inflammatory cytokines while their proliferation and the abundance of regulatory T cells were unaltered. The numbers of inflammatory monocytes and reactive microglia in the central nervous system (CNS) in MRlysM mice were significantly lower and they adopted an M2-polarized phenotype based on their gene expression profile, presumably explaining the ameliorated neuroinflammation. Our results indicate that the MR in myeloid cells plays a critical role for CNS autoimmunity, providing a rational to interfere with diseases such as MS by pharmacologically targeting this receptor."],["dc.identifier.doi","10.3389/fimmu.2017.01319"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14800"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59025"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.publisher","Frontiers Media S.A."],["dc.relation.eissn","1664-3224"],["dc.relation.issn","1664-3224"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","Deletion of the Mineralocorticoid Receptor in Myeloid Cells Attenuates Central Nervous System Autoimmunity"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2517"],["dc.bibliographiccitation.journal","Brain"],["dc.bibliographiccitation.lastpage","2530"],["dc.bibliographiccitation.volume","132"],["dc.contributor.author","Cotte, S."],["dc.contributor.author","von Ahsen, Nicolas"],["dc.contributor.author","Kruse, Niels"],["dc.contributor.author","Huber, B."],["dc.contributor.author","Winkelmann, Alexander"],["dc.contributor.author","Zettl, Uwe K."],["dc.contributor.author","Starck, Michaela"],["dc.contributor.author","Koenig, N."],["dc.contributor.author","Tellez, N."],["dc.contributor.author","Doerr, J."],["dc.contributor.author","Paul, Friedemann"],["dc.contributor.author","Zipp, Frauke"],["dc.contributor.author","Luehder, Fred"],["dc.contributor.author","Koepsell, Hermann"],["dc.contributor.author","Pannek, H."],["dc.contributor.author","Montalban, Xavier"],["dc.contributor.author","Gold, Ralf"],["dc.contributor.author","Chan, A."],["dc.date.accessioned","2018-11-07T11:24:34Z"],["dc.date.available","2018-11-07T11:24:34Z"],["dc.date.issued","2009"],["dc.description.abstract","Escalation therapy with mitoxantrone (MX) in highly active multiple sclerosis is limited by partially dose-dependent side-effects. Predictors of therapeutic response may result in individualized risk stratification and MX dosing. ATP-binding cassette-transporters ABCB1 and ABCG2 represent multi-drug resistance mechanisms involved in active cellular MX efflux. Here, we investigated the role of ABC-gene single nucleotide polymorphisms (SNPs) for clinical MX response, corroborated by experimental in vitro and in vivo data. Frequencies of ABCB1 2677GT, 3435CT and five ABCG2-SNPs were analysed in 832 multiple sclerosis patients (Germany, Spain) and 264 healthy donors. Using a flow-cytometry-based in vitro assay, MX efflux in leukocytes from individuals with variant alleles in both ABC-genes (designated genotype ABCB1/ABCG2-L(ow), 22.2 of patients) was 37.7 lower than from individuals homozygous for common alleles (ABCB1/ABCG2-H(igh), P 0.05, 14.8 of patients), resulting in genotype-dependent MX accumulation and cell death. Addition of glucocorticosteroids (GCs) inhibited MX efflux in vitro. ABC-transporters were highly expressed in leukocyte subsets, glial and neuronal cells as well as myocardium, i.e. cells/tissues potentially affected by MX therapy. In vivo significance was further corroborated in experimental autoimmune encephalomyelitis in Abcg2(/) animals. Using a MX dose titrated to be ineffective in wild-type animals, disease course and histopathology in Abcg2(/) mice were strongly ameliorated. Retrospective clinical analysis in MX monotherapy patients (n 155) used expanded disability status scale, relapse rate and multiple sclerosis functional composite as major outcome parameters. The clinical response rate [overall 121 of 155 patients (78.1)] increased significantly with genotypes associated with decreasing ABCB1/ABCG2-function [ABCB1/ABCG2-H 15/24 (62.5) responders, ABCB1/ABCG2-I(ntermediate) 78/98 (79.6), ABCB1/ABCG2-L 28/33 (84.8), exact Cochran-Armitage test P 0.039]. The odds ratio for response was 1.9 (95 CI 1.03.5) with each increase in ABCB1/ABCG2 score (from ABCB1/ABCG2-H to I-, and I to L). In 36 patients with severe cardiac or haematological side effects no statistically relevant difference in genotype frequency was observed. However, one patient with biopsy proven cardiomyopathy only after 24 mg/m(2) MX exhibited a rare genotype with variant, partly homozygous alleles in 3 ABC-transporter genes. In conclusion, SNPs in ABC-transporter genes may serve as pharmacogenetic markers associated with clinical response to MX therapy in multiple sclerosis. Combined MX/GC-treatment warrants further investigation."],["dc.description.sponsorship","Merck Serono, Germany"],["dc.identifier.doi","10.1093/brain/awp164"],["dc.identifier.isi","000269963600021"],["dc.identifier.pmid","19605531"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6073"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/56436"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Oxford Univ Press"],["dc.relation.issn","0006-8950"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","ABC-transporter gene-polymorphisms are potential pharmacogenetic markers for mitoxantrone response in multiple sclerosis"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e4643"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","PLoS ONE"],["dc.bibliographiccitation.volume","4"],["dc.contributor.author","Gogishvili, Tea"],["dc.contributor.author","Langenhorst, Daniela"],["dc.contributor.author","Luehder, Fred"],["dc.contributor.author","Elias, Fernando"],["dc.contributor.author","Elflein, Karin"],["dc.contributor.author","Dennehy, Kevin M."],["dc.contributor.author","Gold, Ralf"],["dc.contributor.author","Huenig, Thomas"],["dc.date.accessioned","2018-11-07T08:32:35Z"],["dc.date.available","2018-11-07T08:32:35Z"],["dc.date.issued","2009"],["dc.description.abstract","Superagonistic CD28-specific monoclonal antibodies (CD28SA) are highly effective activators of regulatory T-cells (Treg cells) in rats, but a first-in-man trial of the human CD28SA TGN1412 resulted in an unexpected cytokine release syndrome. Using a novel mouse anti-mouse CD28SA, we re-investigate the relationship between Treg activation and systemic cytokine release. Treg activation by CD28SA was highly efficient but depended on paracrine IL-2 from CD28SA-stimulated conventional T-cells. Systemic cytokine levels were innocuous, but depletion of Treg cells prior to CD28SA stimulation led to systemic release of proinflammatory cytokines, indicating that in rodents, Treg cells effectively suppress the inflammatory response. Since the human volunteers of the TGN1412 study were not protected by this mechanism, we also tested whether corticosteroid prophylaxis would be compatible with CD28SA induced Treg activation. We show that neither the expansion nor the functional activation of Treg cells is affected by high-dose dexamethasone sufficient to control systemic cytokine release. Our findings warn that preclinical testing of activating biologicals in rodents may miss cytokine release syndromes due to the rapid and efficacious response of the rodent Treg compartment, and suggest that polyclonal Treg activation is feasible in the presence of antiphlogistic corticosteroid prophylaxis."],["dc.identifier.doi","10.1371/journal.pone.0004643"],["dc.identifier.isi","000265487800023"],["dc.identifier.pmid","19247496"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/5818"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/17376"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Public Library Science"],["dc.relation.issn","1932-6203"],["dc.rights","CC BY 2.5"],["dc.rights.uri","https://creativecommons.org/licenses/by/2.5"],["dc.title","Rapid Regulatory T-Cell Response Prevents Cytokine Storm in CD28 Superagonist Treated Mice"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e0148428"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","PLoS ONE"],["dc.bibliographiccitation.volume","11"],["dc.contributor.author","Andresen, Lena"],["dc.contributor.author","Theodorou, Konstantina"],["dc.contributor.author","Gruenewald, Sarah"],["dc.contributor.author","Czech-Zechmeister, Bozena"],["dc.contributor.author","Koennecke, Birte"],["dc.contributor.author","Luehder, Fred"],["dc.contributor.author","Trendelenburg, George"],["dc.date.accessioned","2018-11-07T10:18:18Z"],["dc.date.available","2018-11-07T10:18:18Z"],["dc.date.issued","2016"],["dc.description.abstract","Toll-like receptors (TLRs) are central sensors for the inflammatory response in ischemia-reperfusion injury. We therefore investigated whether TLR4 inhibition could be used to treat stroke in a standard model of focal cerebral ischemia. Anti-TLR4/MD2-antibody (mAb clone MTS510) blocked TLR4-induced cell activation in vitro, as reported previously. Here, different routes of MTS510 application in vivo were used to study the effects on stroke outcome up to 2d after occlusion of the middle cerebral artery (MCAO) for 45min in adult male C57Bl/6 wild-type mice. Improved neurological performance, reduced infarct volumes, and reduced brain swelling showed that intravascular application of MTS510 had a protective effect in the model of 45min MCAO. Evaluation of potential long-term adverse effects of anti-TLR4-mAb-treament revealed no significant deleterious effect on infarct volumes nor neurological deficit after 14d of reperfusion in a mild model of stroke (15min MCAO). Interestingly, inhibition of TLR4 resulted in an altered adaptive immune response at 48 hours after reperfusion. We conclude that blocking TLR4 by the use of specific mAb is a promising strategy for stroke therapy. However, long-term studies with increased functional sensitivity, larger sampling sizes and use of other species are required before a clinical use could be envisaged."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2016"],["dc.identifier.doi","10.1371/journal.pone.0148428"],["dc.identifier.isi","000369554000092"],["dc.identifier.pmid","26849209"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/12842"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/41412"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Public Library Science"],["dc.relation.issn","1932-6203"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Evaluation of the Therapeutic Potential of Anti-TLR4-Antibody MTS510 in Experimental Stroke and Significance of Different Routes of Application"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Frontiers in Immunology"],["dc.bibliographiccitation.volume","12"],["dc.contributor.author","Bier, Jasmina"],["dc.contributor.author","Steiger, Sebastian M."],["dc.contributor.author","Reichardt, Holger M."],["dc.contributor.author","Lühder, Fred"],["dc.date.accessioned","2021-07-05T14:57:53Z"],["dc.date.available","2021-07-05T14:57:53Z"],["dc.date.issued","2021"],["dc.description.abstract","Induction of T cell apoptosis constitutes a major mechanism by which therapeutically administered glucocorticoids (GCs) suppress inflammation and associated clinical symptoms, for instance in multiple sclerosis (MS) patients suffering from an acute relapse. The sensitivity of T cells to GC action depends on their maturation and activation status, but the precise effect of antigen-priming in a pathological setting has not been explored. Here we used transgenic and congenic mouse models to compare GC-induced apoptosis between naïve and antigen-specific effector T cells from mice immunized with a myelin peptide. Antigen-primed effector T cells were protected from the pro-apoptotic activity of the synthetic GC dexamethasone in a dose-dependent manner, which resulted in their accumulation relative to naïve T cells in vitro and in vivo . Notably, the differential sensitivity of T cells to GC-induced apoptosis correlated with their expression level of the anti-apoptotic proteins Bcl-2 and Bcl-X L and a loss of the mitochondrial membrane potential. Moreover, accumulation of antigen-primed effector T cells following GC treatment in vitro resulted in an aggravated disease course in an adoptive transfer mouse model of MS in vivo , highlighting the clinical relevance of the observed phenomenon. Collectively, our data indicate that antigen-priming influences the T cells’ sensitivity to therapeutically applied GCs in the context of inflammatory diseases."],["dc.description.abstract","Induction of T cell apoptosis constitutes a major mechanism by which therapeutically administered glucocorticoids (GCs) suppress inflammation and associated clinical symptoms, for instance in multiple sclerosis (MS) patients suffering from an acute relapse. The sensitivity of T cells to GC action depends on their maturation and activation status, but the precise effect of antigen-priming in a pathological setting has not been explored. Here we used transgenic and congenic mouse models to compare GC-induced apoptosis between naïve and antigen-specific effector T cells from mice immunized with a myelin peptide. Antigen-primed effector T cells were protected from the pro-apoptotic activity of the synthetic GC dexamethasone in a dose-dependent manner, which resulted in their accumulation relative to naïve T cells in vitro and in vivo . Notably, the differential sensitivity of T cells to GC-induced apoptosis correlated with their expression level of the anti-apoptotic proteins Bcl-2 and Bcl-X L and a loss of the mitochondrial membrane potential. Moreover, accumulation of antigen-primed effector T cells following GC treatment in vitro resulted in an aggravated disease course in an adoptive transfer mouse model of MS in vivo , highlighting the clinical relevance of the observed phenomenon. Collectively, our data indicate that antigen-priming influences the T cells\\’ sensitivity to therapeutically applied GCs in the context of inflammatory diseases."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2021"],["dc.identifier.doi","10.3389/fimmu.2021.671258"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/87763"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-441"],["dc.relation.eissn","1664-3224"],["dc.relation.orgunit","Institut für Neuroimmunologie und Multiple-Sklerose-Forschung"],["dc.rights","CC BY 4.0"],["dc.title","Protection of Antigen-Primed Effector T Cells From Glucocorticoid-Induced Apoptosis in Cell Culture and in a Mouse Model of Multiple Sclerosis"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2921"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","Cells"],["dc.bibliographiccitation.volume","10"],["dc.contributor.affiliation","Reichardt, Sybille D.; 1Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, 37073 Göttingen, Germany; sybille.reichardt@med.uni-goettingen.de (S.D.R.); agathe.amouret@med.uni-goettingen.de (A.A.); chiara.muzzi@med.uni-goettingen.de (C.M.)"],["dc.contributor.affiliation","Amouret, Agathe; 1Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, 37073 Göttingen, Germany; sybille.reichardt@med.uni-goettingen.de (S.D.R.); agathe.amouret@med.uni-goettingen.de (A.A.); chiara.muzzi@med.uni-goettingen.de (C.M.)"],["dc.contributor.affiliation","Muzzi, Chiara; 1Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, 37073 Göttingen, Germany; sybille.reichardt@med.uni-goettingen.de (S.D.R.); agathe.amouret@med.uni-goettingen.de (A.A.); chiara.muzzi@med.uni-goettingen.de (C.M.)"],["dc.contributor.affiliation","Vettorazzi, Sabine; 2Institute of Comparative Molecular Endocrinology, Ulm University, 89081 Ulm, Germany; sabine.vettorazzi@uni-ulm.de (S.V.); jan.tuckermann@uni-ulm.de (J.P.T.)"],["dc.contributor.affiliation","Tuckermann, Jan P.; 2Institute of Comparative Molecular Endocrinology, Ulm University, 89081 Ulm, Germany; sabine.vettorazzi@uni-ulm.de (S.V.); jan.tuckermann@uni-ulm.de (J.P.T.)"],["dc.contributor.affiliation","Lühder, Fred; 3Institute for Neuroimmunology and Multiple Sclerosis Research, University Medical Center Göttingen, 37075 Göttingen, Germany; fred.luehder@med.uni-goettingen.de"],["dc.contributor.affiliation","Reichardt, Holger M.; 1Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, 37073 Göttingen, Germany; sybille.reichardt@med.uni-goettingen.de (S.D.R.); agathe.amouret@med.uni-goettingen.de (A.A.); chiara.muzzi@med.uni-goettingen.de (C.M.)"],["dc.contributor.author","Reichardt, Sybille D."],["dc.contributor.author","Amouret, Agathe"],["dc.contributor.author","Muzzi, Chiara"],["dc.contributor.author","Vettorazzi, Sabine"],["dc.contributor.author","Tuckermann, Jan P."],["dc.contributor.author","Lühder, Fred"],["dc.contributor.author","Reichardt, Holger M."],["dc.date.accessioned","2022-01-11T14:07:51Z"],["dc.date.available","2022-01-11T14:07:51Z"],["dc.date.issued","2021"],["dc.date.updated","2022-02-09T13:20:27Z"],["dc.description.abstract","For more than 70 years, glucocorticoids (GCs) have been a powerful and affordable treatment option for inflammatory diseases. However, their benefits do not come without a cost, since GCs also cause side effects. Therefore, strong efforts are being made to improve their therapeutic index. In this review, we illustrate the mechanisms and target cells of GCs in the pathogenesis and treatment of some of the most frequent inflammatory disorders affecting the central nervous system, the gastrointestinal tract, the lung, and the joints, as well as graft-versus-host disease, which often develops after hematopoietic stem cell transplantation. In addition, an overview is provided of novel approaches aimed at improving GC therapy based on chemical modifications or GC delivery using nanoformulations. GCs remain a topic of highly active scientific research despite being one of the oldest class of drugs in medical use."],["dc.description.abstract","For more than 70 years, glucocorticoids (GCs) have been a powerful and affordable treatment option for inflammatory diseases. However, their benefits do not come without a cost, since GCs also cause side effects. Therefore, strong efforts are being made to improve their therapeutic index. In this review, we illustrate the mechanisms and target cells of GCs in the pathogenesis and treatment of some of the most frequent inflammatory disorders affecting the central nervous system, the gastrointestinal tract, the lung, and the joints, as well as graft-versus-host disease, which often develops after hematopoietic stem cell transplantation. In addition, an overview is provided of novel approaches aimed at improving GC therapy based on chemical modifications or GC delivery using nanoformulations. GCs remain a topic of highly active scientific research despite being one of the oldest class of drugs in medical use."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2021"],["dc.identifier.doi","10.3390/cells10112921"],["dc.identifier.eissn","2073-4409"],["dc.identifier.pii","cells10112921"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/97878"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-507"],["dc.relation.eissn","2073-4409"],["dc.relation.orgunit","Institut für Zelluläre und Molekulare Immunologie"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0/"],["dc.title","The Role of Glucocorticoids in Inflammatory Diseases"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2248"],["dc.bibliographiccitation.journal","Brain"],["dc.bibliographiccitation.lastpage","2263"],["dc.bibliographiccitation.volume","133"],["dc.contributor.author","Linker, Ralf A."],["dc.contributor.author","Lee, De-Hyung"],["dc.contributor.author","Demir, Seray"],["dc.contributor.author","Wiese, Stefan"],["dc.contributor.author","Kruse, Niels"],["dc.contributor.author","Siglienti, Ines"],["dc.contributor.author","Gerhardt, Ellen"],["dc.contributor.author","Neumann, Harald"],["dc.contributor.author","Sendtner, Michael"],["dc.contributor.author","Luehder, Fred"],["dc.contributor.author","Gold, Ralf"],["dc.date.accessioned","2018-11-07T08:40:38Z"],["dc.date.available","2018-11-07T08:40:38Z"],["dc.date.issued","2010"],["dc.description.abstract","Brain-derived neurotrophic factor plays a key role in neuronal and axonal survival. Brain-derived neurotrophic factor is expressed in the immune cells in lesions of experimental autoimmune encephalomyelitis and multiple sclerosis, thus potentially mediating neuroprotective effects. We investigated the functional role of brain-derived neurotrophic factor in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Mice deficient for brain-derived neurotrophic factor in immune cells displayed an attenuated immune response in the acute phase of experimental autoimmune encephalomyelitis, but progressive disability with enhanced axonal loss in the chronic phase of the disease. In mice deficient for central nervous system-derived brain-derived neurotrophic factor via glial fibrillary acidic protein-crescentin-mediated deletion, a more severe course of experimental autoimmune encephalomyelitis and an overall increased axonal loss was observed. In a lentiviral approach, injection of brain-derived neurotrophic factor-overexpressing T cells led to a less severe course of experimental autoimmune encephalomyelitis and direct axonal protection. Our data imply a functional role of brain-derived neurotrophic factor in autoimmune demyelination by mediating axon protection."],["dc.identifier.doi","10.1093/brain/awq179"],["dc.identifier.isi","000280982700010"],["dc.identifier.pmid","20826430"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6203"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/19277"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Oxford Univ Press"],["dc.relation.issn","0006-8950"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Functional role of brain-derived neurotrophic factor in neuroprotective autoimmunity: therapeutic implications in a model of multiple sclerosis"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","8486"],["dc.bibliographiccitation.issue","16"],["dc.bibliographiccitation.journal","International Journal of Molecular Sciences"],["dc.bibliographiccitation.volume","22"],["dc.contributor.affiliation","Hülskötter, Kirsten; \t\t \r\n\t\t Department of Pathology, University of Veterinary Medicine Hannover, Foundation, 30559 Hannover, Germany, kirsten.huelskoetter@tiho-hannover.de\t\t \r\n\t\t Center for Systems Neuroscience, 30559 Hannover, Germany, kirsten.huelskoetter@tiho-hannover.de"],["dc.contributor.affiliation","Lühder, Fred; \t\t \r\n\t\t Institute for Neuroimmunology and Multiple Sclerosis Research, University Medical Center Göttingen, 37075 Göttingen, Germany, fred.luehder@med.uni-goettingen.de"],["dc.contributor.affiliation","Flügel, Alexander; \t\t \r\n\t\t Center for Systems Neuroscience, 30559 Hannover, Germany, fluegel@med.uni-goettingen.de\t\t \r\n\t\t Institute for Neuroimmunology and Multiple Sclerosis Research, University Medical Center Göttingen, 37075 Göttingen, Germany, fluegel@med.uni-goettingen.de"],["dc.contributor.affiliation","Herder, Vanessa; \t\t \r\n\t\t Department of Pathology, University of Veterinary Medicine Hannover, Foundation, 30559 Hannover, Germany, vanessa.herder@tiho-hannover.de\t\t \r\n\t\t Center for Systems Neuroscience, 30559 Hannover, Germany, vanessa.herder@tiho-hannover.de"],["dc.contributor.affiliation","Baumgärtner, Wolfgang; \t\t \r\n\t\t Department of Pathology, University of Veterinary Medicine Hannover, Foundation, 30559 Hannover, Germany, Wolfgang.baumgaertner@tiho-hannover.de\t\t \r\n\t\t Center for Systems Neuroscience, 30559 Hannover, Germany, Wolfgang.baumgaertner@tiho-hannover.de"],["dc.contributor.author","Hülskötter, Kirsten"],["dc.contributor.author","Lühder, Fred"],["dc.contributor.author","Flügel, Alexander"],["dc.contributor.author","Herder, Vanessa"],["dc.contributor.author","Baumgärtner, Wolfgang"],["dc.date.accessioned","2021-10-01T09:58:26Z"],["dc.date.available","2021-10-01T09:58:26Z"],["dc.date.issued","2021"],["dc.date.updated","2022-09-04T01:37:29Z"],["dc.description.abstract","Tamoxifen is frequently used in murine knockout systems with CreER/LoxP. Besides possible neuroprotective effects, tamoxifen is described as having a negative impact on adult neurogenesis. The present study investigated the effect of a high-dose tamoxifen application on Theiler’s murine encephalomyelitis virus (TMEV)-induced hippocampal damage. Two weeks after TMEV infection, 42% of the untreated TMEV-infected mice were affected by marked inflammation with neuronal loss, whereas 58% exhibited minor inflammation without neuronal loss. Irrespective of the presence of neuronal loss, untreated mice lacked TMEV antigen expression within the hippocampus at 14 days post-infection (dpi). Interestingly, tamoxifen application 0, 2 and 4, or 5, 7 and 9 dpi decelerated virus elimination and markedly increased neuronal loss to 94%, associated with increased reactive astrogliosis at 14 dpi. T cell infiltration, microgliosis and expression of water channels were similar within the inflammatory lesions, regardless of tamoxifen application. Applied at 0, 2 and 4 dpi, tamoxifen had a negative impact on the number of doublecortin (DCX)-positive cells within the dentate gyrus (DG) at 14 dpi, without a long-lasting effect on neuronal loss at 147 dpi. Thus, tamoxifen application during a TMEV infection is associated with transiently increased neuronal loss in the hippocampus, increased reactive astrogliosis and decreased neurogenesis in the DG."],["dc.description.abstract","Tamoxifen is frequently used in murine knockout systems with CreER/LoxP. Besides possible neuroprotective effects, tamoxifen is described as having a negative impact on adult neurogenesis. The present study investigated the effect of a high-dose tamoxifen application on Theiler’s murine encephalomyelitis virus (TMEV)-induced hippocampal damage. Two weeks after TMEV infection, 42% of the untreated TMEV-infected mice were affected by marked inflammation with neuronal loss, whereas 58% exhibited minor inflammation without neuronal loss. Irrespective of the presence of neuronal loss, untreated mice lacked TMEV antigen expression within the hippocampus at 14 days post-infection (dpi). Interestingly, tamoxifen application 0, 2 and 4, or 5, 7 and 9 dpi decelerated virus elimination and markedly increased neuronal loss to 94%, associated with increased reactive astrogliosis at 14 dpi. T cell infiltration, microgliosis and expression of water channels were similar within the inflammatory lesions, regardless of tamoxifen application. Applied at 0, 2 and 4 dpi, tamoxifen had a negative impact on the number of doublecortin (DCX)-positive cells within the dentate gyrus (DG) at 14 dpi, without a long-lasting effect on neuronal loss at 147 dpi. Thus, tamoxifen application during a TMEV infection is associated with transiently increased neuronal loss in the hippocampus, increased reactive astrogliosis and decreased neurogenesis in the DG."],["dc.identifier.doi","10.3390/ijms22168486"],["dc.identifier.pii","ijms22168486"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/90061"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-469"],["dc.relation.eissn","1422-0067"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0/"],["dc.title","Tamoxifen Application Is Associated with Transiently Increased Loss of Hippocampal Neurons following Virus Infection"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","247"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Acta Neuropathologica"],["dc.bibliographiccitation.lastpage","258"],["dc.bibliographiccitation.volume","123"],["dc.contributor.author","Lee, De-Hyung"],["dc.contributor.author","Geyer, Eva"],["dc.contributor.author","Flach, Anne-Christine"],["dc.contributor.author","Jung, Klaus"],["dc.contributor.author","Gold, Ralf"],["dc.contributor.author","Fluegel, Alexander"],["dc.contributor.author","Linker, Ralf A."],["dc.contributor.author","Luehder, Fred"],["dc.date.accessioned","2018-11-07T09:13:35Z"],["dc.date.available","2018-11-07T09:13:35Z"],["dc.date.issued","2012"],["dc.description.abstract","Brain-derived neurotrophic factor (BDNF) is involved in neuronal and glial development and survival. While neurons and astrocytes are its main cellular source in the central nervous system (CNS), bioactive BDNF is also expressed in immune cells and in lesions of multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). Previous data revealed that BDNF exerts neuroprotective effects in myelin oligodendrocyte glycoprotein-induced EAE. Using a conditional knock-out model with inducible deletion of BDNF, we here show that clinical symptoms and structural damage are increased when BDNF is absent during the initiation phase of clinical EAE. In contrast, deletion of BDNF later in the disease course of EAE did not result in significant changes, either in the disease course or in axonal integrity. Bone marrow chimeras revealed that the deletion of BDNF in the CNS alone, with no deletion of BDNF in the infiltrating immune cells, was sufficient for the observed effects. Finally, the therapeutic effect of glatiramer acetate, a well-characterized disease-modifying drug with the potential to modulate BDNF expression, was partially reversed in mice in which BDNF was deleted shortly before the onset of disease. In summary, our data argue for an early window of therapeutic opportunity where modulation of BDNF may exert neuroprotective effects in experimental autoimmune demyelination."],["dc.identifier.doi","10.1007/s00401-011-0890-3"],["dc.identifier.isi","000301855900008"],["dc.identifier.pmid","22009304"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/7120"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/27216"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Springer"],["dc.relation.issn","0001-6322"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Central nervous system rather than immune cell-derived BDNF mediates axonal protective effects early in autoimmune demyelination"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e1003906"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","PLoS Pathogens"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Ndlovu, Hlumani"],["dc.contributor.author","Darby, Mathew"],["dc.contributor.author","Froelich, Monika"],["dc.contributor.author","Horsnell, William"],["dc.contributor.author","Lühder, Fred"],["dc.contributor.author","Hünig, Thomas"],["dc.contributor.author","Brombacher, Frank"],["dc.date.accessioned","2018-11-07T09:44:15Z"],["dc.date.available","2018-11-07T09:44:15Z"],["dc.date.issued","2014"],["dc.description.abstract","IL-13 driven Th2 immunity is indispensable for host protection against infection with the gastrointestinal nematode Nippostronglus brasiliensis. Disruption of CD28 mediated costimulation impairs development of adequate Th2 immunity, showing an importance for CD28 during the initiation of an immune response against this pathogen. In this study, we used global CD28(-/-) mice and a recently established mouse model that allows for inducible deletion of the cd28 gene by oral administration of tamoxifen (CD28(-/lox)Cre(+/-)+TM) to resolve the controversy surrounding the requirement of CD28 costimulation for recall of protective memory responses against pathogenic infections. Following primary infection with N. brasiliensis, CD28(-/-) mice had delayed expulsion of adult worms in the small intestine compared to wild-type C57BL/6 mice that cleared the infection by day 9 post-infection. Delayed expulsion was associated with reduced production of IL-13 and reduced serum levels of antigen specific IgG1 and total IgE. Interestingly, abrogation of CD28 costimulation in CD28(-/lox)Cre(+/-) mice by oral administration of tamoxifen prior to secondary infection with N. brasiliensis resulted in impaired worm expulsion, similarly to infected CD28(-/-) mice. This was associated with reduced production of the Th2 cytokines IL-13 and IL-4, diminished serum titres of antigen specific IgG1 and total IgE and a reduced CXCR5(+) T-FH cell population. Furthermore, total number of CD4(+) T cells and B220(+) B cells secreting Th1 and Th2 cytokines were significantly reduced in CD28(-/-) mice and tamoxifen treated CD28(-/lox)Cre(+/-) mice compared to C57BL/6 mice. Importantly, interfering with CD28 costimulatory signalling before re-infection impaired the recruitment and/or expansion of central and effector memory CD4(+) T cells and follicular B cells to the draining lymph node of tamoxifen treated CD28(-/lox)Cre(+/-) mice. Therefore, it can be concluded that CD28 costimulation is essential for conferring host protection during secondary N. brasiliensis infection. Author Summary CD28 is an important costimulatory molecule, involved in the activation of naive T cells, enhancing cytokine production, preventing T cell anergy and apoptosis. Furthermore, CD28 plays a crucial role in the organisation of secondary lymphoid tissue by assisting in the recruitment of T cells into the B cell follicles, thus promoting germinal center formation, isotype switching and B cell maturation. The requirement of CD28 costimulatory signalling during recall of memory responses against infections has remained controversial. Hence, here we utilised a mouse model that allowed for inducible deletion of the cd28 gene (CD28(-/lox)Cre(+/-)) by oral administration of tamoxifen to resolve this controversy. CD28(-/-) mice and mice given tamoxifen prior to secondary infection failed to expel adult N. brasiliensis worms. This was related to reduced production of the Th2 cytokines IL-13 and IL-4, diminished type 2 antibody titres, and a reduced number of memory CD4(+) T cells. In summary, CD28 is crucial for protection against N. brasiliensis secondary infection and plays a key role in the recruitment of T-FH cells, memory CD4(+) T cells and follicular B cells."],["dc.identifier.doi","10.1371/journal.ppat.1003906"],["dc.identifier.isi","000332085900044"],["dc.identifier.pmid","24516382"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/9895"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/34352"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.notes.submitter","Najko"],["dc.relation.issn","1553-7374"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Inducible Deletion of CD28 Prior to Secondary Nippostrongylus brasiliensis Infection Impairs Worm Expulsion and Recall of Protective Memory CD4(+) T Cell Responses"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]