Pathogenetic role of tissue factor in graft-versus-host disease

Abstract

Graft-versus-host disease (GVHD) is a serious complication after allogeneic stem cell transplantation, the mechanism of it is still not elucidated. Recent findings suggest that host endothelial cells are a target of alloreactive donor cytotoxic T lymphocytes in GVHD and tissue factor (TF) plays an important role not only in coagulation-inflammation cycle, but also in transplant immunology. We postulate TF expression in vascular endothelial cells(VEC) may play an pivotal role in the pathogenesis of GVHD. TF gene andprotein expression in target organs of GVHD in aGVHD mice was significantly elevated compared to that of controls as determined by real-time PCR and Western blotting. Allogeneic CD4^+^T cell and CD8^+^T cells enhanced TF, VCAM-1, TNF-[alpha], IFN-[gamma] and IL-6 expression in TNF-[alpha] prestimulated HUVECs compared to controls as determined by flowcytometry and real-time PCR. JNK and p38MAPK mediated allogeneic T cells-induced TF expression in HUVECs. These effects were largely prevented by monoclonal antibody against TF, SB203580 and SP600125. In concert, these data provide strong evidence that upregulated TF expression is related to tissue damage caused by GVHD, TF isthe key factor in GVHD mediated by endothelial cells and allogeneic T cells-induced TF and consecutive proinflammatory cytokines expression in VEC contribute to the pathogenesis of GVHD.