Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Vascular endothelial cells are entirely exposed and damaged during the pathogenesis of acute GVHD (aGVHD). Defibrotide (DF) is a mixture of single-stranded oligonucleotides that has several pharmacologic effects that contribute to its endothelial protective properties. B10.BR mice were conditioned, followed by the infusion of donor C57BL/6J T cell-depleted bone marrow cells with or without splenocytes. The mice were either treated with DF or appropriate controls daily for the first week and then 3 times per week thereafter. Allogeneic DF-treated recipients demonstrated significantly better survival with reduced clinical GVHD. Significantly reduced organ pathology in the gut was associated with significantly decreased T cell infiltration in the ileum and colon on day +28. Serum cytokine analysis revealed significantly reduced levels of TNF and IL-6 at day +7 and of TNF at day +28 in allogeneic DF-treated recipients. Significantly reduced levels of ICAM-1 and angiopoietin-2 in serum and reduced VCAM-1 and HCAM levels in the ileum and colon of allogeneic DF-treated recipients were observed. Improved survival was seen in the graft-versus-leukemia (GVL) model (C3H.SW into C57BL/6J mice with C1498-luc). Through its anti-inflammatory and endothelial protective effects, DF treatment reduces the severity of aGVHD while not impairing GVL activity.
Keywords: Defibrotide; Graft-versus-host-disease; Mice.
Published by Elsevier Inc.