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

Abstract

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.

The importance of neovascularization and its inhibition for allogeneic hematopoietic stem cell transplantation

“…71 In another murine model of acute GVHD that did not involve any conditioning treatment, the earliest detectable oral mucosa lesion was apoptosis of the ECs from chorionic capillaries, which precedes basal keratinocyte apoptosis. 72 Moreover, EC death and lymphocytic inflammation preceded epithelial injury during the development of acute GVHD. These findings collectively show that ECs are damaged by activated alloreactive donor T cells.…”

Angiogenic factors and inflammation in steroid-refractory acute graft-vs-host disease

“…The phenomenon of endothelial cell damage and subsequent vascular response possibly arises in a manner similar to the classic description of the pathogenesis of aGVHD itself, with endothelial damage as a result of the conditioning regimen, followed by T-cell activation against host endothelial cells, followed by apparent neovascularization in an effort to repair damaged tissues. Interestingly, epithelial injury – the clinical hallmark of aGVHD – might be considered a secondary event after initial endothelial cell damage caused by alloreactive T cells [16, 17]. The dichotomy of endothelial cell damage and neovascularization in aGVHD remains an area of active investigation.…”

Peripheral tolerance can be modified by altering KLF2-regulated Treg migration

“…Of note, statins have an immunosuppressive effect on endothelial cells, including decreased MHC class II expression, decreased expression of P-selectin and CD40, increased surface expression of complement inhibitory molecules, and increased production of nitric oxide (31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). Because the endothelial compartment contributes to symptoms of aGVHD (42)(43)(44)(45), these pleiotropic effects precluded the systemic use of simvastatin to test Treg-mediated tolerance. Instead, CD62L low Tregs were treated with simvastatin or control vehicle ex vivo before cotransfer with effector T cells into allogeneic hosts.…”