The role of adhesion molecules in human leukocyte attachment to porcine vascular endothelium: Implications for xenotransplantation

Many obstacles still prevent successful xenotransplantation of porcine dono r organs. When hyperacute rejection is averted, transplanted pig organs are subject to acute vascular and cellular rejection. In autologous systems, l eukocyte recruitment into inflamed tissues involves selectins, integrins, a nd Ig family members. To determine whether these mechanisms allow human leu kocytes to effectively enter porcine grafts, the pathways by which human le ukocytes adhere to TNF-alpha-stimulated porcine aortic endothelium were exa mined under static and physiologic flow conditions. L-selectin and E-select in had overlapping functions in neutrophil capture and rolling, whereas Ab blockade of E-selectin and the beta(2) integrins inhibited firm arrest of r olling neutrophils. Combined blockade of selectins and beta(2) integrins re sulted in negligible human neutrophil attachment to pig endothelium, Lympho cyte attachment to porcine endothelium was primarily L-selectin mediated, w hereas beta(2) integrin and VCAM-l/very late Ag-4 (VLA-4) interactions prom oted static adhesion. Concurrent beta(2) integrin, VLA-4, VCAM-1, and L-sel ectin blockade completely inhibited lymphocyte attachment. Thus, interactio ns between leukocyte-endothelial cell adhesion receptor pairs remained rema rkably intact across the human-porcine species barrier. Moreover, disruptin g the adhesion cascade may impair the ability of human leukocytes to infilt rate a transplanted porcine organ during rejection.