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Activated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells.
Ranjan, Satish Goihl, Alexander Kohli, Shrey Gadi, Ihsan Pierau, Mandy Shahzad, Khurrum Gupta, Dheerendra Bock, Fabian Wang, Hongjie Shaikh, Haroon
Ranjan, Satish
Goihl, Alexander
Kohli, Shrey
Gadi, Ihsan
Pierau, Mandy
Shahzad, Khurrum
Gupta, Dheerendra
Bock, Fabian
Wang, Hongjie
Shaikh, Haroon
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2017-08-21
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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.
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Activated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells. 2017, 8 (1):311 Nat Commun
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en
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2041-1723