Drugs modulating endothelial function after transplantation.

Endothelial cells play a vital role in the success or failure of a transplant procedure. The procedure itself can be viewed as a series of insults that damages the endothelium thereby triggering an inflammatory cascade that may, if uncontrolled, drive the proliferative and fibrotic processes characteristic of chronic graft vasculopathy. Unfortunately, many immunosuppressant agents contribute to this process. Glucocorticoids and the calcineurin inhibitor cyclosporine induce endothelial dysfunction, and although tacrolimus may not have the same disruptive effects on endothelial function as cyclosporine, its endothelial activity is still being established. In contrast, antiproliferative agents slow the proliferation and migration of endothelial cells and so help protect against graft vasculopathy. Researchers agree that endothelial cell dysfunction is a potentially treatable stage in the multifactorial process of graft vasculopathy and rejection. A number of cardiovascular agents (statins, angiotensin converting enzyme inhibitors, calcium channel blockers), immunoregulatory drugs, and dietary compounds have been shown to have beneficial effects on endothelial function. We briefly review the evidence supporting their use as protection for endothelial cells in transplant recipients.

Dendritic cell adhesion is enhanced on endothelial cells preexposed to calcineurin inhibitors.

Chronic rejection remains a major complication in solid organ transplantation. Host alloreactive T cells (TC) can be activated by donor dendritic cells (DCs; direct allorecognition) or by recipient DCs (indirect allorecognition). A fundamental aspect of DC function is vascular invasion to present donor antigens to recipient naive TC in secondary lymphoid organs. We investigated the impact of calcineurin inhibitors on DC binding and transmigration to allogeneic human microvascular endothelial cells (ECs) with and without blocking of specific adhesion molecules. Recipient immature DCs were generated by culturing CD14 human peripheral blood monocytes with GM-CSF and IL-4. DC adhesion and transmigration were investigated on allogeneic ECs preincubated with increasing concentrations of cyclosporine and tacrolimus. Experiments were repeated in the presence of blocking antibodies against LFA-1, PECAM-1, VCAM-1, and ICAM-1. Endothelial stimulation with cyclosporine A (100 and 300 ng/mL) and tacrolimus (15 ng/mL) significantly enhanced DC-EC adhesion and transmigration (P<0.01). LFA-1 blockade on DCs significantly reduced cyclosporine- and tacrolimus-induced DC adhesion (P<0.001). VCAM-1 blockade on ECs partially reversed cyclosporine-induced DC adhesion (P<0.001), whereas DC adhesion under tacrolimus exposure was significantly decreased by ICAM-1 (P<0.01) and PECAM-1 (P<0.001) blockade. DC binding and transmigration on allogeneic ECs exposed to calcineurin inhibitors is concentration-dependently increased. Different adhesion molecule patterns on ECs are responsible for enhanced DC invasion under cyclosporine and tacrolimus exposure. We speculate that long-term immunosuppression mediates enhanced invasion of recipient DCs to the donor organ and therefore may aggravate chronic rejection.

Endothelial determinants of dendritic cell adhesion and migration: new implications for vascular diseases.

OBJECTIVE: Atherosclerosis is a chronic disease triggered by endothelial injury and sustained by inflammation. Dendritic cells (DCs) are critical for the cell-mediated arm of an immune response and are known to influence inflammatory immunity. A fundamental aspect of DC function is their capacity to adhere and migrate through vascular endothelial cells (ECs). We investigated the role of endothelial activation and dysregulation of the NO pathway on DC adhesion and migration. METHODS AND RESULTS: We discovered that DC adhesion and migration are modulated by changes in endothelial function. DC adhesion and transmigration were markedly increased after exposing ECs to hypoxia, oxidized low density lipoprotein, or tumor necrosis factor-alpha. Specifically, inhibition of endothelial NO synthase increased DC binding and transmigration. L-Arginine or 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition partially decreased DC-EC interaction. CONCLUSIONS: The results of this study suggest that the adhesion and migration of DCs are increased by stimuli known to accelerate atherogenesis. Vice versa, augmentation of endothelial NO synthase activity prevents DC adhesion. These findings may provide insight into the inflammatory processes occurring in atherosclerosis. Because DCs control immunity, regulating DC-EC interaction may be relevant to inflammation and atherogenesis.