Activated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells.

2.50
Hdl Handle:
http://hdl.handle.net/10033/621082
Title:
Activated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells.
Authors:
Ranjan, Satish; Goihl, Alexander; Kohli, Shrey; Gadi, Ihsan; Pierau, Mandy; Shahzad, Khurrum; Gupta, Dheerendra; Bock, Fabian; Wang, Hongjie; Shaikh, Haroon; Kähne, Thilo; Reinhold, Dirk; Bank, Ute; Zenclussen, Ana C; Niemz, Jana; Schnöder, Tina M; Brunner-Weinzierl, Monika; Fischer, Thomas; Kalinski, Thomas; Schraven, Burkhart; Luft, Thomas; Huehn, Jochen; Naumann, Michael; Heidel, Florian H; Isermann, Berend
Abstract:
Graft-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.
Affiliation:
Helmholtz Centre for infection research GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
Citation:
Activated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells. 2017, 8 (1):311 Nat Commun
Journal:
Nature communications
Issue Date:
21-Aug-2017
URI:
http://hdl.handle.net/10033/621082
DOI:
10.1038/s41467-017-00169-4
PubMed ID:
28827518
Type:
Article
Language:
en
ISSN:
2041-1723
Appears in Collections:
publications of the division experimentelle Immunologie (EXIM); publications of the department of immune control (IMMK)

Full metadata record

DC FieldValue Language
dc.contributor.authorRanjan, Satishen
dc.contributor.authorGoihl, Alexanderen
dc.contributor.authorKohli, Shreyen
dc.contributor.authorGadi, Ihsanen
dc.contributor.authorPierau, Mandyen
dc.contributor.authorShahzad, Khurrumen
dc.contributor.authorGupta, Dheerendraen
dc.contributor.authorBock, Fabianen
dc.contributor.authorWang, Hongjieen
dc.contributor.authorShaikh, Haroonen
dc.contributor.authorKähne, Thiloen
dc.contributor.authorReinhold, Dirken
dc.contributor.authorBank, Uteen
dc.contributor.authorZenclussen, Ana Cen
dc.contributor.authorNiemz, Janaen
dc.contributor.authorSchnöder, Tina Men
dc.contributor.authorBrunner-Weinzierl, Monikaen
dc.contributor.authorFischer, Thomasen
dc.contributor.authorKalinski, Thomasen
dc.contributor.authorSchraven, Burkharten
dc.contributor.authorLuft, Thomasen
dc.contributor.authorHuehn, Jochenen
dc.contributor.authorNaumann, Michaelen
dc.contributor.authorHeidel, Florian Hen
dc.contributor.authorIsermann, Berenden
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.en
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

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