Sustained function of genetically modified porcine lungs in an ex vivo model of pulmonary xenotransplantation.
BACKGROUND
Xenotransplantation could provide a solution to the donor shortage that is currently the major barrier to solid-organ transplantation. The ability to breed pigs with multiple genetic modifications provides a unique opportunity to explore the immunologic challenges of pulmonary xenotransplantation.


METHODS
Explanted lungs from wild-type and 3 groups of genetically modified pigs were studied: (i) α1,3-galactosyltransferase gene knockout (GTKO); (ii) GTKO pigs expressing the human complementary regulatory proteins CD55 and CD59 (GTKO/CD55-59); and (iii) GTKO pigs expressing both CD55-59 and CD39 (GTKO/CD55-59/CD39). The physiologic, immunologic and histologic properties of porcine lungs were evaluated on an ex vivo rig after perfusion with human blood.


RESULTS
Lungs from genetically modified pigs demonstrated stable pulmonary vascular resistance and better oxygenation of the perfusate, and survived longer than wild-type lungs. Physiologic function was inversely correlated with the degree of platelet sequestration into the xenograft. Despite superior physiologic profiles, lungs from genetically modified pigs still showed evidence of intravascular thrombosis and coagulopathy after perfusion with human blood.


CONCLUSIONS
The ability to breed pigs with multiple genetic modifications, and to evaluate lung physiology and histology in real-time on an ex vivo rig, represent significant advances toward better understanding the challenges inherent to pulmonary xenotransplantation.
(a)Department of Allergy, Immunology and Respiratory Medicine, The Alfred Hospital, Melbourne. Electronic address: g.westall@alfred.org.au.
Glen P
GP
Westall
Browyn J
BJ
Levvey
Evelyn
E
Salvaris
Julian
J
Gooi
Sylvana
S
Marasco
Frank
F
Rosenfeldt
Chris
C
Egan
Robin
R
McEgan Ccp
Mark
M
Mennen
Prue
P
Russell
Simon C
SC
Robson
Mark B
MB
Nottle
Karen M
KM
Dwyer
Greg I
GI
Snell
Peter J
PJ
Cowan
D000818:Animals; D030801:Animals, Genetically Modified / Q000502:physiology*; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001081:Apyrase / Q000235:genetics / Q000378:metabolism; D018958:CD55 Antigens / Q000235:genetics / Q000378:metabolism; D018957:CD59 Antigens / Q000235:genetics / Q000378:metabolism; D005260:Female; D005700:Galactosyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D055786:Gene Knockout Techniques; D006801:Humans; D008168:Lung / Q000502:physiology*; D016040:Lung Transplantation; D008297:Male; D023421:Models, Animal; D010477:Perfusion; D013552:Swine / Q000235:genetics*; D014183:Transplantation, Heterologous; D014655:Vascular Resistance / Q000502:physiology
D015703:Antigens, CD; D018958:CD55 Antigens; D018957:CD59 Antigens; D005700:Galactosyltransferases; C530267:alpha-1,3-galactosyltransferase 1, porcine; D001081:Apyrase; C067869:CD39 antigen
Gal knockout; ex vivo lung perfusion; genetically engineered; hyperacute rejection; lung; swine; xenotransplantation