title: Dendritic cell adhesion is enhanced on endothelial cells preexposed to calcineurin inhibitors.
abstract: 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.
authors.affiliation: Department of Surgery, Division of Transplantation Surgery, School of Medicine, University Hospital, University Rostock, Rostock, Germany. christoph.schlichting@drschlichting.de
authors.forename: Christoph L
authors.initials: CL
authors.lastname: Schlichting
authors.forename: Wolfgang D
authors.initials: WD
authors.lastname: Schareck
authors.forename: Michael
authors.initials: M
authors.lastname: Weis
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D065095:Calcineurin Inhibitors; D002448:Cell Adhesion / Q000187:drug effects*; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006084:Graft Rejection / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D065095:Calcineurin Inhibitors; D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D018950:Lipopolysaccharide Receptors; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016572:Cyclosporine; D016559:Tacrolimus