Endothelial injury mediated by cytotoxic T lymphocytes and loss of microvessels in chronic graft versus host disease

Background Vascular endothelial cells form the interface between recipient tissues and circulating alloreactive donor T cells after allogeneic stem cell transplantation. Vascular injury has been seen in patients with acute graft versus host disease (GVHD) in the skin. We aimed to see whether vascular injury mediated by cytotoxic T lymphocytes and microvessel loss arises in patients with chronic GVHD. Methods We investigated eight patients with acute GVHD and ten with chronic GVHD for signs of endothelial injury and microvessel loss by measurement of von Willebrand factor (vWF) in plasma and blood vessel density in biopsy samples taken from lesional skin. Controls consisted of nine patients without GVHD who survived for longer than 100 days and nine healthy people. Inflammation and endothelial injury were assessed in selected samples by immunostaining for CD8 T cells, activated cytotoxic T lymphocytes, and vascular endothelial cells. Findings We identified more extensive loss of microvessels in the skin of patients with GVHD (median 66 capilllaries/mm(2); IQR 16-98) than of healthy controls (205 capilliaries/mm(2); 157-226; p=0.005). Patients with GVHD had higher concentrations of vWF (238%; 168-288) than did those without GVHD (102%; 88-118; p=0.0005). Perivascular CD8 T cell infiltrates in skin correlated with vWF plasma concentrations in patients with GVHD (p=0.01), and activated cytotoxic T lymphocytes and endothelial injury were present in these same samples. Interpretation Host endothelial cells are a target of alloreactive donor cytotoxic T lymphocytes. Substantial blood vessel loss may lead to impaired blood perfusion and tissue fibrosis, the hallmark lesion of chronic GVHD.