Hyperacute rejection is attenuated in GalT knockout swine lungs perfused ex vivo with human blood.
BACKGROUND
Hyperacute rejection (HAR) is one of the principal obstacles to successful xenotransplantation. Homozygous alpha-1,3-galactosyltransferase knockout (GalT-KO) miniature swine now offer the prospect of overcoming this barrier to xenotransplantation. In this study, the short-term function of GalT-KO swine lungs was evaluated in a well-established ex vivo model of swine-to-human lung xenotransplantation.


METHODS
Lungs from homozygous GalT-KO swine (n = 3) and control lungs from pigs of the background strain used to create the GalT-KO pig line (n = 2) were perfused ex vivo with freshly collected heparinized human blood. Graft function was assessed by various physiologic measurements, serial histologic and immunohistochemical evaluation, and assays of complement and platelet activation.


RESULTS
Xenoperfused control swine lungs exhibited HAR with graft survival times <5 minutes. In contrast, GalT-KO swine lungs retained their function for approximately 2 hours, on average. GalT-KO swine lungs showed decreased complement and platelet activation compared with controls. Nonetheless, activation of complement and coagulation cascades was not completely eliminated in the GalT-KO swine lungs.


CONCLUSIONS
The survival of xenoperfused GalT-KO swine lungs was significantly prolonged, as compared with control lungs expressing Gal. This appears to have been due largely to substantially reduced complement activation. Nonetheless, the xenoperfused GalT-KO lungs still showed some evidence of complement fixation and intravascular coagulopathy by the time of graft demise.
Schroeder
C
C
Department of Surgery, Division of Thoracic Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, USA.
Allan
J S
JS
Nguyen
B-N
BN
Wu
G
G
Zhang
T
T
Azimzadeh
A M
AM
Madsen
J C
JC
Schuurman
H-J
HJ
Sachs
D H
DH
Pierson
R N
RN
D000208:Acute Disease; D000818:Animals; D005700:Galactosyltransferases / Q000235:genetics*; D017353:Gene Deletion; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D016040:Lung Transplantation / Q000276:immunology*; D012129:Respiratory Function Tests; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*
D005700:Galactosyltransferases; C047006:N-acetyllactosaminide alpha-1,3-galactosyltransferase