The role of adhesion molecules in human leukocyte attachment to porcine vascular endothelium: implications for xenotransplantation.
Many obstacles still prevent successful xenotransplantation of porcine donor organs. When hyperacute rejection is averted, transplanted pig organs are subject to acute vascular and cellular rejection. In autologous systems, leukocyte recruitment into inflamed tissues involves selectins, integrins, and Ig family members. To determine whether these mechanisms allow human leukocytes to effectively enter porcine grafts, the pathways by which human leukocytes adhere to TNF-alpha-stimulated porcine aortic endothelium were examined under static and physiologic flow conditions. L-selectin and E-selectin had overlapping functions in neutrophil capture and rolling, whereas Ab blockade of E-selectin and the beta2 integrins inhibited firm arrest of rolling neutrophils. Combined blockade of selectins and beta2 integrins resulted in negligible human neutrophil attachment to pig endothelium. Lymphocyte attachment to porcine endothelium was primarily L-selectin mediated, whereas beta2 integrin and VCAM-1/very late Ag-4 (VLA-4) interactions promoted static adhesion. Concurrent beta2 integrin, VLA-4, VCAM-1, and L-selectin blockade completely inhibited lymphocyte attachment. Thus, interactions between leukocyte-endothelial cell adhesion receptor pairs remained remarkably intact across the human-porcine species barrier. Moreover, disrupting the adhesion cascade may impair the ability of human leukocytes to infiltrate a transplanted porcine organ during rejection.
Robinson
L A
LA
Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
Tu
L
L
Steeber
D A
DA
Preis
O
O
Platt
J L
JL
Tedder
T F
TF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001011:Aorta; D018821:CD18 Antigens / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000502:physiology*; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D019040:E-Selectin / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000502:physiology; D019041:L-Selectin / Q000502:physiology; D007962:Leukocytes / Q000166:cytology*; D008214:Lymphocytes / Q000166:cytology; D009504:Neutrophils / Q000166:cytology; D016201:Receptors, Lymphocyte Homing / Q000502:physiology; D012212:Rheology; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology
D000911:Antibodies, Monoclonal; D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D039041:Integrin alpha4beta1; D016023:Integrins; D016201:Receptors, Lymphocyte Homing; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D019041:L-Selectin