Ex vivo lung model of pig-to-human hyperacute xenograft rejection.

Objective: Our objective was to study lung hyperacute rejection in the pig-to-human xenotransplantation combination.
Methods: Pig lungs were harvested and continuously ventilated and perfused ex vivo, using a neonatal oxygenating system, with either xenogeneic unmodified human blood (n = 6) or autogeneic pig blood (n = 6).
Results: Autoperfused lungs displayed normal hemodynamics, oxygen extraction (arteriovenous oxygen difference), and histologic characteristics throughout the 3-hour study period. By contrast, xenoperfused lungs displayed, within 30 minutes, severe pulmonary hypertension and abolishment of arteriovenous oxygen difference culminating in massive pulmonary edema, hemorrhage, and lung failure after 115 +/- 44.2 minutes of reperfusion. Within 30 minutes, the human blood showed a significant drop of anti-alpha Gal immunoglobulin M and G xenoreactive antibodies (enzyme-linked immunosorbent assay) and complement activity, consumption of clotting factors, and hemolysis; total circulating human immunoglobulins remained substantially normal. Histologically, lungs perfused with human blood were congestive and showed alveolar edema and hemorrhage and multiple fibrin and platelet thrombi obstructing the small pulmonary vessels (arterioles, capillaries, and venules) but not large (segmental or lobar) pulmonary vessels. On immunohistologic examination, deposits of human immunoglobulin M and complement (C1q and C3) proteins were observed on the alveolar capillaries.
Conclusions: This pig-to-human xenograft model suggests that the pig lung perfused with human blood has an early and violent hyperacute rejection that results in irreversible pulmonary dysfunction and failure within approximately 150 minutes of reperfusion.