A Critical Role of Growth Arrest-Specific Gene 6-Mer Axis in the Pathogenesis of Endothelial Damage Contributing to Thrombotic Microangiopathy Associated with Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

Graft-versus-host disease (GVHD) and thrombotic microangiopathy (TMA) are severe complications of allogeneic hematopoietic stem cell transplantation (allo-SCT). Host endothelial cells are targets of alloreactive donor cytotoxic T lymphocytes or various proinflammatory cytokines following allo-SCT, and endothelial damage plays an important role in the pathogenic mechanism(s) of TMA associated with GVHD. However, the detailed mechanism(s) of TMA as well as GVHD have not yet been fully elucidated. Growth arrest-specific (Gas) 6 structurally belongs to the family of plasma vitamin K-dependent proteins working as a cofactor for activated protein C, and has growth factor-like properties through its interaction with receptor tyrosine kinases of the TAM family; Tyro3, Axl, and Mer. Gas6 and the TAM receptor tyrosine kinases have been reported to be associated with systemic inflammatory and autoimmune disorders, as well as hemostatic abnormalities. We hypothesized that Gas6-TAM pathway signaling contributed to endothelial dysfunction in the pathogenesis of TMA associated with GVHD. ELISA showed that the serum levels of Gas6 were markedly increased in the all-SCT patients with grades 2 or 3 GVHD at 21-35 days after stem-cell engraftment. The increased serum levels of Gas6 were also correlated with the elevated D-dimer and plasmin-α2 plasmin inhibitor complex values in the allo-SCT patients. Immunostaining showed that the expression of Gas6 and Mer was significantly upregulated in...
Source: Blood - Category: Hematology Authors: Tags: 701. Experimental Transplantation: Basic Biology, Pre-Clinical Models: Poster III Source Type: research