CD95 ligand-dependant endothelial cell death initiates oral mucosa damage in a murine model of acute graft versus host disease.

Oral mucosa lesions are one of the common pathological consequences of acute graft versus host disease (aGVHD), the major complication of allogeneic bone marrow transplantation caused by mature T lymphocytes of donor origin. Oral mucosa damage in aGVHD is characterized by apoptosis induction in the basal keratinocytes, associated with immune effector T-cell infiltration, but its pathogenesis remains unclear because these lesions might result from the patient conditioning therapy that includes radiation and/or chemotherapy. Here, using a murine model of aGVHD that does not involve any conditioning treatment, we show that the earliest detectable oral mucosa lesion is apoptosis of the endothelial cells from chorion capillaries, which precedes basal keratinocyte apoptosis induction. Neither vascular damage nor epithelial-cell death occurred in recipients of allogeneic lymphocytes from CD95 ligand (CD95L)-defective mice. Our findings indicate that oral mucosa lesions in aGVHD are initiated by endothelial-cell death and require CD95L expression by the allogeneic lymphocytes. This early vascular damage may contribute to the induction of further tissue damage in the oral mucosa, through the induction of hypoxia and vascular leakage of immune cells or soluble proapoptotic mediators.