Hyperacute rejection in ex vivo-perfused porcine lungs transgenic for human complement regulatory proteins.
Inhibition of complement activation via human membrane-associated complement regulators is known to prevent hyperacute rejection in heart and kidney pig-to-primate transplantation. The protective effect of such strategies in pulmonary xenografts, however, seems to be insufficient. In an ex vivo perfusion, model lungs from donor pigs transgenic for human CD55 (n = 6) or human CD59 (n = 5) were perfused with fresh human blood and compared with nontransgenic organs (n = 6). In addition, a soluble complement component 1 esterase inhibitor (C1-Inh) was applied in h-CD55 transgenic lungs (n = 3). In the h-CD55 transgenic group, survival was prolonged (P < 0.05), quality and maximal time of oxygenation significantly improved and pulmonary vascular resistance reduced compared with the control group. There was a decreased sequestration of platelets, less parenchymal injury and reduced deposition of C(5b-9) in the h-CD55 transgenic group. Additional soluble complement inhibition (C1-Inh) did not prolong survival of h-CD55 transgenic lungs. Survival and pulmonary function in lungs expressing h-CD59 was not significantly different from parameters observed in nontransgenic lungs. In this ex vivo model of pig-to-primate lung transplantation, membrane-based complement inhibition resulted in significantly improved pulmonary function. However, minor histopathological injuries observed in these transgenic xenografts suggested only partial protection from pulmonary dysfunction by complement inhibition alone.
Pöling
Jochen
J
Klinik für Herz-,Thorax- und Gefäbchirurgie, Medizinische Hochschule Hannover, Hannover, Germany.
Oezkur
Mehmet
M
Kogge
Karina
K
Mengel
Michael
M
Niemann
Heiner
H
Winkler
Michael
M
Haverich
Axel
A
Wiebe
Karsten
K
D000208:Acute Disease; D000818:Animals; D030801:Animals, Genetically Modified; D001792:Blood Platelets / Q000378:metabolism; D018958:CD55 Antigens / Q000096:biosynthesis / Q000378:metabolism; D018957:CD59 Antigens / Q000096:biosynthesis; D050718:Complement C1 Inhibitor Protein / Q000235:genetics* / Q000378:metabolism; D006084:Graft Rejection; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D016040:Lung Transplantation / Q000379:methods; D010100:Oxygen / Q000378:metabolism; D010313:Partial Pressure; D010477:Perfusion; D013552:Swine; D013997:Time Factors; D019076:Transgenes; D014183:Transplantation, Heterologous / Q000379:methods*
D018958:CD55 Antigens; D018957:CD59 Antigens; D050718:Complement C1 Inhibitor Protein; D010100:Oxygen