Expression of human decay accelerating factor may protect pig lung from hyperacute rejection by human blood.
BACKGROUND
Hyperacute rejection currently prevents clinical application of discordant lung xenografts. Pigs transgenic for human regulators of complement activation offer one promising potential solution to this problem.


METHODS
Using fresh human blood in an ex vivo lung perfusion model, we studied eight different strains of pigs transgenic for human decay accelerating factor. Survival (by blood flow and gas transfer criteria) were correlated with immunohistologic evidence of pulmonary human decay accelerating factor expression and complement activation.


RESULTS
With human blood perfusion, blood flow through the unmodified 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 transgenic pig strains showed no difference from this pattern. Immunohistochemistry for human decay accelerating factor revealed low or no pulmonary expression in these lungs. In contrast, two of five transgenic pig lungs that had significant decay accelerating factor expression demonstrated recovery of pulmonary blood flow within 1 hour, and rejection was delayed, from less than 20 minutes in controls to about 1 hour. Complement activation, particularly the alternative pathway, was inhibited in lungs with high levels of endothelial decay accelerating factor expression.


CONCLUSIONS
Lungs from some strains of pig transgenic for human decay accelerating factor demonstrate incomplete physiologic and histologic protection from hyperacute rejection. Although complement-independent pathogenic mechanisms may present a formidable obstacle, pig lungs transgenic for human complement regulatory proteins may facilitate discordant lung transplantation in human beings.
Pierson
R N
RN
Imutran Ltd., Thoracic Transplant Service, Papworth Hospital, Cambridge, United Kingdom.
Pino-Chavez
G
G
Young
V K
VK
Kaspar-Konig
W
W
White
D J
DJ
Wallwork
J
J
D000818:Animals; D030801:Animals, Genetically Modified; D001769:Blood; D018958:CD55 Antigens / Q000235:genetics*; D003167:Complement Activation / Q000235:genetics / Q000276:immunology; D015870:Gene Expression / Q000502:physiology; D006084:Graft Rejection / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000098:blood supply / Q000473:pathology; D016040:Lung Transplantation / Q000276:immunology* / Q000473:pathology; D010477:Perfusion; D012333:RNA, Messenger / Q000235:genetics; D012039:Regional Blood Flow / Q000502:physiology; D013552:Swine; D014022:Tissue Survival / Q000235:genetics
D018958:CD55 Antigens; D012333:RNA, Messenger