16550
2016
eng
11626
7
article
1
2018-07-24
--
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Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells
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.
Nature Communications
10.1038/ncomms11626
urn:nbn:de:bvb:20-opus-165503
Nature Communications, 2015, 7:11626. DOI: 10.1038/ncomms11626
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Kerstin Göbel
Susann Pankratz
Chloi-Magdalini Asaridou
Alexander M. Herrmann
Stefan Bittner
Monika Merker
Tobias Ruck
Sarah Glumm
Friederike Langhauser
Peter Kraft
Thorsten F. Krug
Johanna Breuer
Martin Herold
Catharina C. Gross
Denise Beckmann
Adelheid Korb-Pap
Michael K. Schuhmann
Stefanie Kuerten
Ioannis Mitroulis
Clemens Ruppert
Marc W. Nolte
Con Panousis
Luisa Klotz
Beate Kehrel
Thomas Korn
Harald F. Langer
Thomas Pap
Bernhard Nieswandt
Heinz Wiendl
Triantafyllos Chavakis
Christoph Kleinschnitz
Sven G. Meuth
eng
uncontrolled
blood coagulation
eng
uncontrolled
factor XII
eng
uncontrolled
neuroinflammation
eng
uncontrolled
dendric cells
Biowissenschaften; Biologie
Medizin und Gesundheit
open_access
Institut für Anatomie und Zellbiologie
Neurologische Klinik und Poliklinik
Rudolf-Virchow-Zentrum
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/16550/Goebel_Nature_Communications.pdf
25956
2021
eng
2835–2840
11
19
article
1
--
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Generation of a humanized FXII knock-in mouse-A powerful model system to test novel anti-thrombotic agents
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.
Journal of Thrombosis and Haemostasis
10.1111/jth.15488
urn:nbn:de:bvb:20-opus-259567
publish
Journal of Thrombosis and Haemostasis 2021, 19(11):2835–2840. DOI: 10.1111/jth.15488
false
true
CC BY-NC: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell 4.0 International
Sarah Beck
David Stegner
Stefan Loroch
Ayesha A. Baig
Vanessa Göb
Cornelia Schumbutzki
Eva Eilers
Albert Sickmann
Frauke May
Marc W. Nolte
Con Panousis
Bernhard Nieswandt
eng
uncontrolled
hemostasis,
eng
uncontrolled
blood coagulation
eng
uncontrolled
factor XII
eng
uncontrolled
animal models
eng
uncontrolled
thrombosis
Medizin und Gesundheit
open_access
Rudolf-Virchow-Zentrum
Institut für Experimentelle Biomedizin
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/25956/Beck_Thrombosis.pdf
16737
2016
eng
e0146783
1
11
article
1
2018-08-27
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The Coagulation Factor XIIa Inhibitor rHA-Infestin-4 Improves Outcome after Cerebral Ischemia/Reperfusion Injury in Rats
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.
PLoS ONE
10.1371/journal.pone.0146783
urn:nbn:de:bvb:20-opus-167370
PLoS ONE 11(1):e0146783 (2016). DOI: 10.1371/journal.pone.0146783
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Jennifer Krupka
Frauke May
Thomas Weimer
Ingo Pragst
Christoph Kleinschnitz
Guido Stoll
Con Panousis
Gerhard Dickneite
Marc W. Nolte
eng
uncontrolled
coagulation factor XIIa
eng
uncontrolled
ischemic stroke
eng
uncontrolled
contact activation system
eng
uncontrolled
FXIIa inhibitor rHA-Infestin
Medizin und Gesundheit
open_access
Neurologische Klinik und Poliklinik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/16737/Krupka_PLoS_ONE.PDF