The role of antibodies and von Willebrand factor in discordant pulmonary xenotransplantation.
Pulmonary xenotransplantation is one potential solution to the paucity of donors but is currently limited by rapid failure of the graft. Unlike cardiac and renal xenotransplants, pulmonary xenografts release large quantities of swine von Willebrand factor (vWF). Swine vWF binds xenoreactive antibodies and is capable of activating primate platelets. The contribution of swine vWF to lung xenograft dysfunction is not entirely clear. To probe the role vWF plays in xenograft dysfunction, we traced the fate of xenoantibodies in vWF+ and von Willebrand factor-deficient (vWFD) swine lungs. These studies showed that the vast majority of xenoantibodies bind the vWF released from the vWF+ swine lung, and thus do not remain bound on lung endothelium. The vWF complexed to xenoantibody remained capable of aggregating primate platelets. With this information, we performed swine-to-baboon lung transplants using vWF+ and vWFD donors. Without vWF present to complex xenoantibodies, a picture of hyperacute rejection more typical of heart and kidney xenografts, with antibody deposition along the graft endothelium, interstitial hemorrhage, and edema occurred. These findings suggest that porcine vWF plays a major role in the pathogenesis of pulmonary xenograft dysfunction, and suggests promising strategies to treat lung xenograft dysfunction.
Lau
Christine L
CL
Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
Cantu
Edward
E
Gonzalez-Stawinski
Gonzalo V
GV
Holzknecht
Zoie E
ZE
Nichols
Timothy C
TC
Posther
Katherine E
KE
Rayborn
Cory A
CA
Platt
Jeffrey L
JL
Parker
William
W
Davis
R Duane
RD
D000818:Animals; D000910:Antibodies, Heterophile / Q000276:immunology*; D004187:Disaccharides / Q000276:immunology; D006801:Humans; D016040:Lung Transplantation / Q000276:immunology* / Q000473:pathology; D023421:Models, Animal; D010215:Papio; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*; D014841:von Willebrand Factor / Q000235:genetics / Q000276:immunology*
D000910:Antibodies, Heterophile; D004187:Disaccharides; D014841:von Willebrand Factor; C055075:galactosyl-(1-3)galactose