Fas Ligand Overexpression on Allograft Endothelium Inhibits Inflammatory Cell Infiltration and Transplant-Associated Intimal Hyperplasia

Abstract

Despite recent advances in immunosuppressive therapy, accelerated coronary atherosclerosis remains a major problem in the long-term survival of transplant recipients. Chronic graft vasculopathy is believed to result from recipient inflammatory responses, and it is characterized by early mononuclear cell infiltration of the transplanted vessel. Here we show that endothelial cells can be genetically modified to overexpress functional, cell-surface Fas ligand (FasL) by adenovirus-mediated gene transfer without undergoing self-destruction. In a rodent model of transplant graft vasculopathy, endothelial overexpression of FasL attenuated T cell and macrophage infiltration at 1 wk posttransplantation. These vessels also displayed reduced neointima formation at one and 2 mo posttransplantation. These results indicate that inhibition of the early inflammatory response to allografted vessels by endothelial cell-specific overexpression of FasL may have utility in the treatment of transplant arteriosclerosis.

CD95 engagement induces disseminated endothelial cell apoptosis in vivo: immunopathologic implications

“…26 Our findings indicate that these are only 2 particular examples of a broad in vivo sensitivity of endothelial cells to CD95-mediated death. It should be noted, however, that endothelial cells from some arteries in some tissues and animal species, such as the rabbit ear and rat carotid arteries, have been shown to constitutively express both CD95 and CD95L, 27,28 and very recently, rat carotid artery endothelial cells have been reported to survive adenovirus vector-mediated CD95L overexpression in vivo. 28 Thus, though it is possible that the activation and proinflammatory signals induced by adenovirus vector gene expression have played a role in the repression of CD95-mediated death, these findings indicate that endothelial cells from at least some blood vessels may be resistant to CD95 death signaling induced by local CD95L expression.…”

“…In vivo, endothelial cells have so far been reported to undergo CD95-mediated death in only 2 organs: the liver, in response to agonistic CD95-specific antibody injection, 14,17 as mentioned above, and the eye, in which endothelial cell apoptosis induced by local CD95L expression is involved in the physiologic control of subretinal blood vessel growth after injury. 26 However, endothelial cells from at least some arteries in some animal species, such as rabbit ear and rat carotid arteries, constitutively express both CD95 and CD95L, 27,28 and rat carotid artery endothelial cells have been recently reported to survive adenovirus vector-mediated CD95L overexpression. 28 Thus, whether in vivo sensitivity to CD95-mediated death signaling is restricted to endothelial cells from particular blood vessels in a few tissues or is a general characteristic of endothelial cells from most blood vessels throughout the body remains so far unknown.…”

“…26 However, endothelial cells from at least some arteries in some animal species, such as rabbit ear and rat carotid arteries, constitutively express both CD95 and CD95L, 27,28 and rat carotid artery endothelial cells have been recently reported to survive adenovirus vector-mediated CD95L overexpression. 28 Thus, whether in vivo sensitivity to CD95-mediated death signaling is restricted to endothelial cells from particular blood vessels in a few tissues or is a general characteristic of endothelial cells from most blood vessels throughout the body remains so far unknown.…”

“…26 However, endothelial cells from at least some arteries in some animal species, such as rabbit ear and rat carotid arteries, constitutively express both CD95 and CD95L, 27,28 and rat carotid artery endothelial cells have been recently reported to survive adenovirus vector-mediated CD95L overexpression. 28 Thus, whether in vivo sensitivity to CD95-mediated death signaling is restricted to endothelial cells from particular blood vessels in a few tissues or is a general characteristic of endothelial cells from most blood vessels throughout the body remains so far unknown.Tumor necrosis factor-␣, another member of the TNF/CD95L family, has been reported to induce disseminated endothelial cell apoptosis 29 that precedes induction of apoptosis in additional cell types and lethal multiorgan failure. Here we show that CD95L shares with TNF-␣ the capacity to cause disseminated endothelial cell apoptosis and vascular lesions, through a mechanism that does not depend on TNF-␣ expression.…”

Endothelial Recovery

“…The latter phenomenon, although relatively understudied, appears to be a significant component of neointimal lesions, 7 which can be inhibited by targeting leukocytes themselves 36 or by restoring endothelial barrier function. 37 An intact endothelium appears to be nature's means of preventing intimal lesion formation. The study by Hedman et al 1 unveils a strategy designed to recapitulate nature, rather that thwart it, enhancing endothelial function as a primary strategy for restenosis prevention.…”