Transgenic human decay accelerating factor makes normal pigs function as a concordant species.
BACKGROUND
Increasing interest has focused on xenotransplantation as a potential solution to the organ shortage. To overcome hyperacute rejection, pigs have been produced that are transgenic for human decay accelerating factor (DAF). For the evaluation of the effects of human DAF, an ex vivo working heart model was used.


METHODS
We compared hemodynamic performance of four transgenic pig hearts (group A) with that of four Landrace pig hearts (group B) and eight rhesus monkey hearts (group C). For perfusion fresh blood had been taken from healthy volunteers. From the coronary sinus effluent, samples were taken for the determination of 6-keto prostaglandin F1 alpha, prostaglandin E2, creatine phosphokinase, and lactate dehydrogenase, respectively. Hemodynamic parameters were measured continuously for 150 minutes after the start. After 15 minutes of reperfusion, the Langendorff-mode was switched to the working heart model. After hearts failed to pump against the afterload column, experiments were terminated, and tissue sections were taken for electron microscopy.


RESULTS
Groups A and C showed superior cardiac performance as measured by stroke work index (SWI) that exceeded group B by 2.5 to 3 times (p < 0.05). In all three groups the SWI slowly decreased during perfusion. In group B, SWI decreased to a minimum as early as 90 minutes after the start. In all groups, 6-keto prostaglandin F1 alpha and prostaglandin E2 as indicators of endothelial cell activation increased. In group B, however, the levels exceeded those of groups A and C by six and nine times, respectively (p < 0.05). As markers of myocardial damage, creatine phosphokinase and lactate dehydrogenase increased in all groups. But again levels in group B exceeded those of groups A and C by four to five times (p < 0.05). Electron microscopy revealed single cell necrosis in group B, whereas groups A and C showed interstitial edema only.


CONCLUSIONS
Our experiments indicate a crucial role of DAF in preventing rejection in discordant species combinations. Transgenic human DAF seems to inhibit successfully complement-mediated damage to the endothelial cell, thus preventing endothelial activation and consequently myocardial damage. Transgenic human DAF makes a discordant species (pig) function as a concordant species, that is, hyperacute rejection does not occur.
Schmoeckel
M
M
Department of Cardiac Surgery, Klinikum Grosshadern, University of Munich, Germany.
Nollert
G
G
Shahmohammadi
M
M
Müller-Höcker
J
J
Young
V K
VK
Kasper-König
W
W
White
D J
DJ
Hammer
C
C
Reichart
B
B
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified / Q000502:physiology*; D001803:Blood Transfusion; D018958:CD55 Antigens / Q000235:genetics / Q000502:physiology*; D003402:Creatine Kinase / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D006084:Graft Rejection / Q000503:physiopathology / Q000517:prevention & control; D006321:Heart / Q000502:physiology*; D006334:Heart Function Tests; D016027:Heart Transplantation / Q000502:physiology; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D013552:Swine; D014183:Transplantation, Heterologous
D018958:CD55 Antigens; D015121:6-Ketoprostaglandin F1 alpha; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase; D015232:Dinoprostone