TRANSGENIC HUMAN DECAY-ACCELERATING FACTOR MAKES NORMAL PIGS FUNCTIONAS A CONCORDANT SPECIES

Background: Increasing interest has focused on xenotransplantation as a potential solution to the organ shortage. To overcome hyperacute rej ection, pigs have been produced that are transgenic for human decay ac celerating factor (DAF). For the evaluation of the effects of human DA F, an ex vivo working heart model was used. Methods: We compared hemod ynamic performance of four transgenic pig hearts (group A) with that o f four Landrace pig hearts (group B) and eight rhesus monkey hearts (g roup C). For perfusion fresh blood had been taken from healthy volunte ers. From the coronary sinus effluent, samples were taken for the dete rmination of 6-keto prostaglandin F-1 alpha, prostaglandin E-2, creati ne 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 t o the working heart model. After hearts failed to pump against the aft erload column, experiments were terminated, and tissue sections were t aken for electron microscopy. Results: Groups A and C showed superior cardiac performance as measured by stroke work index (SWI) that exceed ed group B by 2.5 to 3 times (p < 0.05). In all three groups the SWI s lowly decreased during perfusion. In group B, SWI decreased to a minim um as early as 90 minutes after the start. In all groups, 6-keto prost aglandin F-1 alpha and prostaglandin E-2 as indicators of endothelial cell activation increased. In group B, however, the levels exceeded th ose of groups A and C by six and nine times, respectively (p < 0.05). As markers of myocardial damage, creatine phosphokinase and lactate de hydrogenase increased in all groups. But again levels in group B excee ded 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 in dicate a crucial role of DAF in preventing rejection in discordant spe cies combinations. Transgenic human DAF seems to inhibit successfully complement-mediated damage to the endothelial cell, thus preventing en dothelial activation and consequently myocardial damage. Transgenic hu man DAF makes a discordant species (pig) function as a concordant spec ies, that is, hyperacute rejection does not occur.