@article{GoebelPankratzAsaridouetal.2016, author = {G{\"o}bel, Kerstin and Pankratz, Susann and Asaridou, Chloi-Magdalini and Herrmann, Alexander M. and Bittner, Stefan and Merker, Monika and Ruck, Tobias and Glumm, Sarah and Langhauser, Friederike and Kraft, Peter and Krug, Thorsten F. and Breuer, Johanna and Herold, Martin and Gross, Catharina C. and Beckmann, Denise and Korb-Pap, Adelheid and Schuhmann, Michael K. and Kuerten, Stefanie and Mitroulis, Ioannis and Ruppert, Clemens and Nolte, Marc W. and Panousis, Con and Klotz, Luisa and Kehrel, Beate and Korn, Thomas and Langer, Harald F. and Pap, Thomas and Nieswandt, Bernhard and Wiendl, Heinz and Chavakis, Triantafyllos and Kleinschnitz, Christoph and Meuth, Sven G.}, title = {Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells}, series = {Nature Communications}, volume = {7}, journal = {Nature Communications}, number = {11626}, doi = {10.1038/ncomms11626}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165503}, year = {2016}, abstract = {Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS). Recent evidence implicated the crosstalk between coagulation and immunity in CNS autoimmunity. Here we identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein-kinin system, as a specific immune cell modulator. High levels of FXII activity are present in the plasma of MS patients during relapse. Deficiency or pharmacologic blockade of FXII renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by reduced numbers of interleukin-17A-producing T cells. Immune activation by FXII is mediated by dendritic cells in a CD87-dependent manner and involves alterations in intracellular cyclic AMP formation. Our study demonstrates that a member of the plasmatic coagulation cascade is a key mediator of autoimmunity. FXII inhibition may provide a strategy to combat MS and other immune-related disorders.}, language = {en} } @article{BeckStegnerLorochetal.2021, author = {Beck, Sarah and Stegner, David and Loroch, Stefan and Baig, Ayesha A. and G{\"o}b, Vanessa and Schumbutzki, Cornelia and Eilers, Eva and Sickmann, Albert and May, Frauke and Nolte, Marc W. and Panousis, Con and Nieswandt, Bernhard}, title = {Generation of a humanized FXII knock-in mouse-A powerful model system to test novel anti-thrombotic agents}, series = {Journal of Thrombosis and Haemostasis}, volume = {19}, journal = {Journal of Thrombosis and Haemostasis}, number = {11}, doi = {10.1111/jth.15488}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259567}, pages = {2835-2840}, year = {2021}, abstract = {Background Effective inhibition of thrombosis without generating bleeding risks is a major challenge in medicine. Accumulating evidence suggests that this can be achieved by inhibition of coagulation factor XII (FXII), as either its knock-out or inhibition in animal models efficiently reduced thrombosis without affecting normal hemostasis. Based on these findings, highly specific inhibitors for human FXII(a) are under development. However, currently, in vivo studies on their efficacy and safety are impeded by the lack of an optimized animal model expressing the specific target, that is, human FXII. Objective The primary objective of this study is to develop and functionally characterize a humanized FXII mouse model. Methods A humanized FXII mouse model was generated by replacing the murine with the human F12 gene (genetic knock-in) and tested it in in vitro coagulation assays and in in vivo thrombosis models. Results These hF12\(^{KI}\) mice were indistinguishable from wild-type mice in all tested assays of coagulation and platelet function in vitro and in vivo, except for reduced expression levels of hFXII compared to human plasma. Targeting FXII by the anti-human FXIIa antibody 3F7 increased activated partial thromboplastin time dose-dependently and protected hF12\(^{KI}\) mice in an arterial thrombosis model without affecting bleeding times. Conclusion These data establish the newly generated hF12\(^{KI}\) mouse as a powerful and unique model system for in vivo studies on anti-FXII(a) biologics, supporting the development of efficient and safe human FXII(a) inhibitors.}, language = {en} } @article{KrupkaMayWeimeretal.2016, author = {Krupka, Jennifer and May, Frauke and Weimer, Thomas and Pragst, Ingo and Kleinschnitz, Christoph and Stoll, Guido and Panousis, Con and Dickneite, Gerhard and Nolte, Marc W.}, title = {The Coagulation Factor XIIa Inhibitor rHA-Infestin-4 Improves Outcome after Cerebral Ischemia/Reperfusion Injury in Rats}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {1}, doi = {10.1371/journal.pone.0146783}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-167370}, pages = {e0146783}, year = {2016}, abstract = {Background and Purpose Ischemic stroke provokes severe brain damage and remains a predominant disease in industrialized countries. The coagulation factor XII (FXII)-driven contact activation system plays a central, but not yet fully defined pathogenic role in stroke development. Here, we investigated the efficacy of the FXIIa inhibitor rHA-Infestin-4 in a rat model of ischemic stroke using both a prophylactic and a therapeutic approach. Methods For prophylactic treatment, animals were treated intravenously with 100 mg/kg rHA-Infestin-4 or an equal volume of saline 15 min prior to transient middle cerebral artery occlusion (tMCAO) of 90 min. For therapeutic treatment, 100 mg/kg rHA-Infestin-4, or an equal volume of saline, was administered directly after the start of reperfusion. At 24 h after tMCAO, rats were tested for neurological deficits and blood was drawn for coagulation assays. Finally, brains were removed and analyzed for infarct area and edema formation. Results Within prophylactic rHA-Infestin-4 treatment, infarct areas and brain edema formation were reduced accompanied by better neurological scores and survival compared to controls. Following therapeutic treatment, neurological outcome and survival were still improved although overall effects were less pronounced compared to prophylaxis. Conclusions With regard to the central role of the FXII-driven contact activation system in ischemic stroke, inhibition of FXIIa may represent a new and promising treatment approach to prevent cerebral ischemia/reperfusion injury.}, language = {en} }