EXPRESSION OF HUMAN DECAY-ACCELERATING FACTOR MAY PROTECT PIG LUNG FROM HYPERACUTE REJECTION BY HUMAN BLOOD

Background: Hyperacute rejection currently prevents clinical applicati on of discordant lung xenografts. Pigs transgenic for human regulators of complement activation offer one promising potential solution to th is problem. Methods: Using fresh human blood in an ex vivo lung perfus ion model, we studied eight different strains of pigs transgenic for h uman decay accelerating factor. Survival (by blood flow and gas transf er criteria) were correlated with immunohistologic evidence of pulmona ry human decay accelerating factor expression and complement activatio n. Results: With human blood perfusion, blood flow through the unmodif ied pig lung rapidly falls and is not restored by continuous infusion or high-dose bolus of prostacyclin. Airway pressure also rises rapidly and is followed promptly by loss of gas transfer. Four of the transge nic pig strains showed no difference from this pattern. Immunohistoche mistry for human decay accelerating factor revealed low or no pulmonar y expression in these lungs. In contrast, two of five transgenic pig l ungs that had significant decay accelerating factor expression demonst rated recovery of pulmonary blood flow within 1 hour, and rejection wa s delayed, from less than 20 minutes in controls to about 1 hour. Comp lement activation, particularly the alternative pathway, was inhibited in lungs with high levels of endothelial decay accelerating factor ex pression. Conclusions: Lungs from some strains of pig transgenic for h uman decay accelerating factor demonstrate incomplete physiologic and histologic protection from hyperacute rejection. Although complement-i ndependent pathogenic mechanisms may present a formidable obstacle, pi g lungs transgenic for human complement regulatory proteins may facili tate discordant lung transplantation in human beings.