Flügel, Alexander

[["dc.bibliographiccitation.firstpage","1405"],["dc.bibliographiccitation.issue","4"],["dc.bibliographiccitation.journal","Journal of Clinical Investigation"],["dc.bibliographiccitation.lastpage","1416"],["dc.bibliographiccitation.volume","118"],["dc.contributor.author","Mueller, Nora"],["dc.contributor.author","van den Brandt, Jens"],["dc.contributor.author","Odoardi, Francesca"],["dc.contributor.author","Tischner, Denise"],["dc.contributor.author","Herath, Judith"],["dc.contributor.author","Fluegel, Alexander"],["dc.contributor.author","Reichardt, Holger Michael"],["dc.date.accessioned","2018-11-07T11:16:37Z"],["dc.date.available","2018-11-07T11:16:37Z"],["dc.date.issued","2008"],["dc.description.abstract","Administration of the CD28 superagonistic antibody JJ316 is an efficient means to treat autoimmune diseases in rats, but the humanized antibody TGN1412 caused devastating side effects in healthy volunteers during a clinical trial. Here we show that JJ316 treatment of rats induced a dramatic redistribution of T lymphocytes from the periphery to the secondary lymphoid organs, resulting in severe T lymphopenia. Live imaging of secondary lymphoid organs revealed that JJ316 administration almost instantaneously (<2 minutes) arrested T cells in situ. This reduction in T cell motility was accompanied by profound cytoskeletal rearrangements and increased cell size. In addition, surface expression of lymphocyte function-associated antigen-1 was enhanced, endothelial differentiation sphingolipid G protein-coupled receptor 1 and L selectin levels were downregulated, and the cells lost their responsiveness to sphingosine 1-phosphate-directed migration. These proadhesive alterations were accompanied by signs of strong activation, including upregulation of CD25, CD69, CD134, and proinflammatory mediators. However, this did not lead to a cytokine storm similar to the clinical trial. While most of the early changes disappeared within 48 hours, we observed that CD4(+)CD25(+)FoxP3(+) regulatory T cells experienced a second phase of activation, which resulted in massive cell enlargement, extensive polarization, and increased motility. These data suggest that CD28 superagonists elicit 2 qualitatively distinct waves of activation."],["dc.identifier.doi","10.1172/JCI32698"],["dc.identifier.isi","000254588600034"],["dc.identifier.pmid","18357346"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6254"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/54633"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Amer Soc Clinical Investigation Inc"],["dc.relation.issn","0021-9738"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","A CD28 superagonistic antibody elicits 2 functionally distinct waves of T cell activation in rats"],["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.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.firstpage","317"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Acta Neuropathologica"],["dc.bibliographiccitation.lastpage","338"],["dc.bibliographiccitation.volume","132"],["dc.contributor.author","Engelhardt, Britta"],["dc.contributor.author","Carare, Roxana O."],["dc.contributor.author","Bechmann, Ingo"],["dc.contributor.author","Fluegel, Alexander"],["dc.contributor.author","Laman, Jon D."],["dc.contributor.author","Weller, Roy O."],["dc.date.accessioned","2018-11-07T10:09:40Z"],["dc.date.available","2018-11-07T10:09:40Z"],["dc.date.issued","2016"],["dc.description.abstract","Immune privilege of the central nervous system (CNS) has been ascribed to the presence of a blood-brain barrier and the lack of lymphatic vessels within the CNS parenchyma. However, immune reactions occur within the CNS and it is clear that the CNS has a unique relationship with the immune system. Recent developments in high-resolution imaging techniques have prompted a reassessment of the relationships between the CNS and the immune system. This review will take these developments into account in describing our present understanding of the anatomical connections of the CNS fluid drainage pathways towards regional lymph nodes and our current concept of immune cell trafficking into the CNS during immunosurveillance and neuroinflammation. Cerebrospinal fluid (CSF) and interstitial fluid are the two major components that drain from the CNS to regional lymph nodes. CSF drains via lymphatic vessels and appears to carry antigen-presenting cells. Interstitial fluid from the CNS parenchyma, on the other hand, drains to lymph nodes via narrow and restricted basement membrane pathways within the walls of cerebral capillaries and arteries that do not allow traffic of antigen-presenting cells. Lymphocytes targeting the CNS enter by a two-step process entailing receptor-mediated crossing of vascular endothelium and enzyme-mediated penetration of the glia limitans that covers the CNS. The contribution of the pathways into and out of the CNS as initiators or contributors to neurological disorders, such as multiple sclerosis and Alzheimer's disease, will be discussed. Furthermore, we propose a clear nomenclature allowing improved precision when describing the CNS-specific communication pathways with the immune system."],["dc.identifier.doi","10.1007/s00401-016-1606-5"],["dc.identifier.isi","000382011300001"],["dc.identifier.pmid","27522506"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/13744"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/39697"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Springer"],["dc.relation.issn","1432-0533"],["dc.relation.issn","0001-6322"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Vascular, glial, and lymphatic immune gateways of the central nervous system"],["dc.type","review"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","94"],["dc.bibliographiccitation.issue","7269"],["dc.bibliographiccitation.journal","Nature"],["dc.bibliographiccitation.lastpage","U104"],["dc.bibliographiccitation.volume","462"],["dc.contributor.author","Bartholomaeus, Ingo"],["dc.contributor.author","Kawakami, Naoto"],["dc.contributor.author","Odoardi, Francesca"],["dc.contributor.author","Schlaeger, Christian"],["dc.contributor.author","Miljkovic, Djordje"],["dc.contributor.author","Ellwart, Joachim W."],["dc.contributor.author","Klinkert, Wolfgang E. F."],["dc.contributor.author","Fluegel-Koch, Cassandra"],["dc.contributor.author","Issekutz, Thomas B."],["dc.contributor.author","Wekerle, Hartmut"],["dc.contributor.author","Fluegel, Alexander"],["dc.date.accessioned","2018-11-07T11:22:12Z"],["dc.date.available","2018-11-07T11:22:12Z"],["dc.date.issued","2009"],["dc.description.abstract","The tissues of the central nervous system are effectively shielded from the blood circulation by specialized vessels that are impermeable not only to cells, but also to most macromolecules circulating in the blood. Despite this seemingly absolute seclusion, central nervous system tissues are subject to immune surveillance and are vulnerable to autoimmune attacks(1). Using intravital two-photon imaging in a Lewis rat model of experimental autoimmune encephalomyelitis, here we present in real-time the interactive processes between effector T cells and cerebral structures from their first arrival to manifest autoimmune disease. We observed that incoming effector T cells successively scanned three planes. The T cells got arrested to leptomeningeal vessels and immediately monitored the luminal surface, crawling preferentially against the blood flow. After diapedesis, the cells continued their scan on the abluminal vascular surface and the underlying leptomeningeal (pial) membrane. There, the T cells encountered phagocytes that effectively present antigens, foreign as well as myelin proteins. These contacts stimulated the effector T cells to produce pro-inflammatory mediators, and provided a trigger to tissue invasion and the formation of inflammatory infiltrations."],["dc.identifier.doi","10.1038/nature08478"],["dc.identifier.isi","000271419200039"],["dc.identifier.pmid","19829296"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6204"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/55942"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Nature Publishing Group"],["dc.relation.issn","0028-0836"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1930"],["dc.bibliographiccitation.journal","Brain"],["dc.bibliographiccitation.lastpage","1943"],["dc.bibliographiccitation.volume","133"],["dc.contributor.author","Cordiglieri, Chiara"],["dc.contributor.author","Odoardi, Francesca"],["dc.contributor.author","Zhang, B. O."],["dc.contributor.author","Nebel, Merle"],["dc.contributor.author","Kawakami, Naoto"],["dc.contributor.author","Klinkert, Wolfgang E. F."],["dc.contributor.author","Lodygin, Dimtri"],["dc.contributor.author","Luehder, Fred"],["dc.contributor.author","Breunig, Esther"],["dc.contributor.author","Schild, Detlev"],["dc.contributor.author","Ulaganathan, Vijay Kumar"],["dc.contributor.author","Dornmair, Klaus"],["dc.contributor.author","Dammermann, Werner"],["dc.contributor.author","Potter, Barry V. L."],["dc.contributor.author","Guse, Andreas H."],["dc.contributor.author","Fluegel, Alexander"],["dc.date.accessioned","2018-11-07T08:41:30Z"],["dc.date.available","2018-11-07T08:41:30Z"],["dc.date.issued","2010"],["dc.description.abstract","Nicotinic acid adenine dinucleotide phosphate represents a newly identified second messenger in T cells involved in antigen receptor-mediated calcium signalling. Its function in vivo is, however, unknown due to the lack of biocompatible inhibitors. Using a recently developed inhibitor, we explored the role of nicotinic acid adenine dinucleotide phosphate in autoreactive effector T cells during experimental autoimmune encephalomyelitis, the animal model for multiple sclerosis. We provide in vitro and in vivo evidence that calcium signalling controlled by nicotinic acid adenine dinucleotide phosphate is relevant for the pathogenic potential of autoimmune effector T cells. Live two photon imaging and molecular analyses revealed that nicotinic acid adenine dinucleotide phosphate signalling regulates T cell motility and re-activation upon arrival in the nervous tissues. Treatment with the nicotinic acid adenine dinucleotide phosphate inhibitor significantly reduced both the number of stable arrests of effector T cells and their invasive capacity. The levels of pro-inflammatory cytokines interferon-gamma and interleukin-17 were strongly diminished. Consecutively, the clinical symptoms of experimental autoimmune encephalomyelitis were ameliorated. In vitro, antigen-triggered T cell proliferation and cytokine production were evenly suppressed. These inhibitory effects were reversible: after wash-out of the nicotinic acid adenine dinucleotide phosphate antagonist, the effector T cells fully regained their functions. The nicotinic acid derivative BZ194 induced this transient state of non-responsiveness specifically in post-activated effector T cells. Naive and long-lived memory T cells, which express lower levels of the putative nicotinic acid adenine dinucleotide phosphate receptor, type 1 ryanodine receptor, were not targeted. T cell priming and recall responses in vivo were not reduced. These data indicate that the nicotinic acid adenine dinucleotide phosphate/calcium signalling pathway is essential for the recruitment and the activation of autoaggressive effector T cells within their target organ. Interference with this signalling pathway suppresses the formation of autoimmune inflammatory lesions and thus might qualify as a novel strategy for the treatment of T cell mediated autoimmune diseases."],["dc.identifier.doi","10.1093/brain/awq135"],["dc.identifier.isi","000279473900008"],["dc.identifier.pmid","20519328"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6202"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/19486"],["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","Nicotinic acid adenine dinucleotide phosphate-mediated calcium signalling in effector T cells regulates autoimmunity of the central nervous system"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","10678"],["dc.bibliographiccitation.issue","26"],["dc.bibliographiccitation.journal","PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA"],["dc.bibliographiccitation.lastpage","10683"],["dc.bibliographiccitation.volume","106"],["dc.contributor.author","Dammermann, Werner"],["dc.contributor.author","Zhang, B. O."],["dc.contributor.author","Nebel, Merle"],["dc.contributor.author","Cordiglieric, Chiara"],["dc.contributor.author","Odoardi, Francesca"],["dc.contributor.author","Kirchberger, Tanja"],["dc.contributor.author","Kawakami, Naoto"],["dc.contributor.author","Dowden, James"],["dc.contributor.author","Schmid, Frederike"],["dc.contributor.author","Dornmair, Klaus"],["dc.contributor.author","Hohenegger, Martin"],["dc.contributor.author","Fluegel, Alexander"],["dc.contributor.author","Guse, Andreas H."],["dc.contributor.author","Potter, Barry V. L."],["dc.date.accessioned","2018-11-07T08:28:38Z"],["dc.date.available","2018-11-07T08:28:38Z"],["dc.date.issued","2009"],["dc.description.abstract","The nucleotide NAADP was recently discovered as a second messenger involved in the initiation and propagation of Ca2+ signaling in lymphoma T cells, but its impact on primary T cell function is still unknown. An optimized, synthetic, small molecule inhibitor of NAADP action, termed BZ194, was designed and synthesized. BZ194 neither interfered with Ca2+ mobilization by D-myo-inositol 1,4,5-trisphosphate or cyclic ADP-ribose nor with capacitative Ca2+ entry. BZ194 specifically and effectively blocked NAADP-stimulated [H-3] ryanodine binding to the purified type 1 ryanodine receptor. Further, in intact T cells, Ca2+ mobilization evoked by NAADP or by formation of the immunological synapse between primary effector T cells and astrocytes was inhibited by BZ194. Downstream events of Ca2+ mobilization, such as nuclear translocation of \"nuclear factor of activated T cells\" (NFAT), T cell receptor-driven interleukin-2 production, and proliferation in antigen-experienced CD4(+) effector T cells, were attenuated by the NAADP antagonist. Taken together, specific inhibition of the NAADP signaling pathway constitutes a way to specifically and effectively modulate T-cell activation and has potential in the therapy of autoimmune diseases."],["dc.identifier.doi","10.1073/pnas.0809997106"],["dc.identifier.isi","000267564300053"],["dc.identifier.pmid","19541638"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6205"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/16468"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Natl Acad Sciences"],["dc.relation.issn","0027-8424"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","NAADP-mediated Ca2+ signaling via type 1 ryanodine receptor in T cells revealed by a synthetic NAADP antagonist"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Scientific Reports"],["dc.bibliographiccitation.volume","8"],["dc.contributor.author","Zhang, Bo"],["dc.contributor.author","Watt, Joanna M"],["dc.contributor.author","Cordiglieri, Chiara"],["dc.contributor.author","Dammermann, Werner"],["dc.contributor.author","Mahon, Mary F."],["dc.contributor.author","Flügel, Alexander"],["dc.contributor.author","Guse, Andreas H."],["dc.contributor.author","Potter, Barry V. L."],["dc.date.accessioned","2019-07-09T11:51:04Z"],["dc.date.available","2019-07-09T11:51:04Z"],["dc.date.issued","2018"],["dc.description.abstract","Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca2+-releasing second messenger known to date, but the precise NAADP/Ca2+ signalling mechanisms are still controversial. We report the synthesis of small-molecule inhibitors of NAADP-induced Ca2+ release based upon the nicotinic acid motif. Alkylation of nicotinic acid with a series of bromoacetamides generated a diverse compound library. However, many members were only weakly active or had poor physicochemical properties. Structural optimisation produced the best inhibitors that interact specifically with the NAADP/Ca2+ release mechanism, having no effect on Ca2+ mobilized by the other well-known second messengers D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] or cyclic adenosine 5'-diphospho-ribose (cADPR). Lead compound (2) was an efficient antagonist of NAADP-evoked Ca2+ release in vitro in intact T lymphocytes and ameliorated clinical disease in vivo in a rat experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. Compound (3) (also known as BZ194) was synthesized as its bromide salt, confirmed by crystallography, and was more membrane permeant than 2. The corresponding zwitterion (3a), was also prepared and studied by crystallography, but 3 had more desirable physicochemical properties. 3 Is potent in vitro and in vivo and has found widespread use as a tool to modulate NAADP effects in autoimmunity and cardiovascular applications. Taken together, data suggest that the NAADP/Ca2+ signalling mechanism may serve as a potential target for T cell- or cardiomyocyte-related diseases such as multiple sc"],["dc.identifier.doi","10.1038/s41598-018-34917-3"],["dc.identifier.pmid","30425261"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16042"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59869"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.subject.ddc","610"],["dc.title","Small Molecule Antagonists of NAADP-Induced Ca2+ Release in T-Lymphocytes Suggest Potential Therapeutic Agents for Autoimmune Disease"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","275"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Seminars in Immunopathology"],["dc.bibliographiccitation.lastpage","287"],["dc.bibliographiccitation.volume","32"],["dc.contributor.author","Kawakami, Naoto"],["dc.contributor.author","Fluegel, Alexander"],["dc.date.accessioned","2018-11-07T08:40:11Z"],["dc.date.available","2018-11-07T08:40:11Z"],["dc.date.issued","2010"],["dc.description.abstract","Since the first applications of two-photon microscopy in immunology 10 years ago, the number of studies using this advanced technology has increased dramatically. The two-photon microscope allows long-term visualization of cell motility in the living tissue with minimal phototoxicity. Using this technique, we examined brain autoantigen-specific T cell behavior in experimental autoimmune encephalitomyelitis, the animal model of human multiple sclerosis. Even before disease symptoms appear, the autoreactive T cells arrive at their target organ. There they crawl along the intraluminal surface of central nervous system (CNS) blood vessels before they extravasate. In the perivascular environment, the T cells meet phagocytes that present autoantigens. This contact activates the T cells to penetrate deep into the CNS parenchyma, where the infiltrated T cells again can find antigen, be further activated, and produce cytokines, resulting in massive immune cell recruitment and clinical disease."],["dc.identifier.doi","10.1007/s00281-010-0216-x"],["dc.identifier.isi","000281740500006"],["dc.identifier.pmid","20623286"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/5155"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/19167"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Springer"],["dc.relation.issn","1863-2297"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Knocking at the brain's door: intravital two-photon imaging of autoreactive T cell interactions with CNS structures"],["dc.type","review"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]