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

Satish Ranjan, Alexander Goihl, Shrey Kohli, Ihsan Gadi, Mandy Pierau, Khurrum Shahzad, Dheerendra Gupta, Fabian Bock, Hongjie Wang, Haroon Shaikh, Thilo Kähne, Dirk Reinhold, Ute Bank, Ana C. Zenclussen, Jana Niemz, Tina M. Schnöder, Monika Brunner-Weinzierl, Thomas Fischer, Thomas Kalinski, Burkhart Schraven, Thomas Luft, Jochen Huehn, Michael Naumann, Florian H. Heidel and Berend Isermann ()
Additional contact information
Satish Ranjan: Otto-von-Guericke- University Magdeburg
Alexander Goihl: Otto-von-Guericke-University Magdeburg
Shrey Kohli: Otto-von-Guericke- University Magdeburg
Ihsan Gadi: Otto-von-Guericke- University Magdeburg
Mandy Pierau: Otto-von-Guericke-University Magdeburg
Khurrum Shahzad: Otto-von-Guericke- University Magdeburg
Dheerendra Gupta: Otto-von-Guericke- University Magdeburg
Fabian Bock: Otto-von-Guericke- University Magdeburg
Hongjie Wang: Otto-von-Guericke- University Magdeburg
Haroon Shaikh: Otto-von-Guericke- University Magdeburg
Thilo Kähne: Otto-von-Guericke University Magdeburg
Dirk Reinhold: Otto-von-Guericke-University Magdeburg
Ute Bank: Otto-von-Guericke-University Magdeburg
Ana C. Zenclussen: Otto-von-Guericke University
Jana Niemz: Helmholtz Centre for Infection Research (HZI)
Tina M. Schnöder: University Hospital Jena
Monika Brunner-Weinzierl: Otto-von-Guericke-University Magdeburg
Thomas Fischer: Otto-von-Guericke University Magdeburg
Thomas Kalinski: Otto-von-Guericke University Magdeburg
Burkhart Schraven: Otto-von-Guericke-University Magdeburg
Thomas Luft: University of Heidelberg
Jochen Huehn: Helmholtz Centre for Infection Research (HZI)
Michael Naumann: Otto-von-Guericke University Magdeburg
Florian H. Heidel: University Hospital Jena
Berend Isermann: Otto-von-Guericke- University Magdeburg

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00169-4

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