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dc.contributor.authorRanjan, Satish
dc.contributor.authorGoihl, Alexander
dc.contributor.authorKohli, Shrey
dc.contributor.authorGadi, Ihsan
dc.contributor.authorPierau, Mandy
dc.contributor.authorShahzad, Khurrum
dc.contributor.authorGupta, Dheerendra
dc.contributor.authorBock, Fabian
dc.contributor.authorWang, Hongjie
dc.contributor.authorShaikh, Haroon
dc.contributor.authorKähne, Thilo
dc.contributor.authorReinhold, Dirk
dc.contributor.authorBank, Ute
dc.contributor.authorZenclussen, Ana C
dc.contributor.authorNiemz, Jana
dc.contributor.authorSchnöder, Tina M
dc.contributor.authorBrunner-Weinzierl, Monika
dc.contributor.authorFischer, Thomas
dc.contributor.authorKalinski, Thomas
dc.contributor.authorSchraven, Burkhart
dc.contributor.authorLuft, Thomas
dc.contributor.authorHuehn, Jochen
dc.contributor.authorNaumann, Michael
dc.contributor.authorHeidel, Florian H
dc.contributor.authorIsermann, Berend
dc.date.accessioned2017-08-31T13:10:31Z
dc.date.available2017-08-31T13:10:31Z
dc.date.issued2017-08-21
dc.identifier.citationActivated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells. 2017, 8 (1):311 Nat Communen
dc.identifier.issn2041-1723
dc.identifier.pmid28827518
dc.identifier.doi10.1038/s41467-017-00169-4
dc.identifier.urihttp://hdl.handle.net/10033/621082
dc.description.abstractGraft-vs.-host disease (GvHD) is a major complication of allogenic hematopoietic stem-cell(HSC) transplantation. GvHD is associated with loss of endothelial thrombomodulin, but the relevance of this for the adaptive immune response to transplanted HSCs remains unknown. Here we show that the protease-activated protein C (aPC), which is generated by thrombomodulin, ameliorates GvHD aPC restricts allogenic T-cell activation via the protease activated receptor (PAR)2/PAR3 heterodimer on regulatory T-cells (Tregs, CD4(+)FOXP3(+)). Preincubation of pan T-cells with aPC prior to transplantation increases the frequency of Tregs and protects from GvHD. Preincubation of human T-cells (HLA-DR4(-)CD4(+)) with aPC prior to transplantation into humanized (NSG-AB°DR4) mice ameliorates graft-vs.-host disease. The protective effect of aPC on GvHD does not compromise the graft vs. leukaemia effect in two independent tumor cell models. Ex vivo preincubation of T-cells with aPC, aPC-based therapies, or targeting PAR2/PAR3 on T-cells may provide a safe and effective approach to mitigate GvHD.Graft-vs.-host disease is a complication of allogenic hematopoietic stem cell transplantation, and is associated with endothelial dysfunction. Here the authors show that activated protein C signals via PAR2/PAR3 to expand Treg cells, mitigating the disease in mice.
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleActivated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells.en
dc.typeArticleen
dc.contributor.departmentHelmholtz Centre for infection research GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.en
dc.identifier.journalNature communicationsen
refterms.dateFOA2018-06-12T23:27:54Z
html.description.abstractGraft-vs.-host disease (GvHD) is a major complication of allogenic hematopoietic stem-cell(HSC) transplantation. GvHD is associated with loss of endothelial thrombomodulin, but the relevance of this for the adaptive immune response to transplanted HSCs remains unknown. Here we show that the protease-activated protein C (aPC), which is generated by thrombomodulin, ameliorates GvHD aPC restricts allogenic T-cell activation via the protease activated receptor (PAR)2/PAR3 heterodimer on regulatory T-cells (Tregs, CD4(+)FOXP3(+)). Preincubation of pan T-cells with aPC prior to transplantation increases the frequency of Tregs and protects from GvHD. Preincubation of human T-cells (HLA-DR4(-)CD4(+)) with aPC prior to transplantation into humanized (NSG-AB°DR4) mice ameliorates graft-vs.-host disease. The protective effect of aPC on GvHD does not compromise the graft vs. leukaemia effect in two independent tumor cell models. Ex vivo preincubation of T-cells with aPC, aPC-based therapies, or targeting PAR2/PAR3 on T-cells may provide a safe and effective approach to mitigate GvHD.Graft-vs.-host disease is a complication of allogenic hematopoietic stem cell transplantation, and is associated with endothelial dysfunction. Here the authors show that activated protein C signals via PAR2/PAR3 to expand Treg cells, mitigating the disease in mice.


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