Characterization of a pig-to-goat orthotopic lung xenotransplantation model to study beyond hyperacute rejection

A pig-to-goat orthotopic lung xenograft model was developed to test whether depletion of goat xenoreactive antibodies against pig red blood cells woul d prolong pig lung xenograft survival. Methods: Adult goats,vith anti-pig x enoreactive antibodies underwent left pneumonectomy followed by orthotopic transplantation of pig left lung (group 1) or immunodepletion of their xeno reactive antibodies by extracorporeal right pig lung perfusion before trans plantation without (group 2) or with (group 3) complete clampage of the rig ht pulmonary artery. In group 4, goat left lungs were orthotopically transp lanted into pigs and served as negative controls (pig serum does not have a nti-goat xenoreactive antibodies). Each study group included 5 animals. Imm unosuppression in surviving recipients included cyclosporine and azathiopri ne. Results: Group 1 recipients died 7 +/- 3 hours after xenograft reimplan tation of severe pulmonary hypertension and dysfunction and vasogenic shock ,,vith little evidence of histologic xenograft injury, Group 2 xenografts h ad a stable circulatory and respiratory function on reperfusion and survive d 9 +/- 4 days. Group 3 animals also tolerated complete occlusion of the ri ght pulmonary artery, and xenografts assured the total respiratory support for 4 +/- 1 days. After immunodepletion, goat serum showed no detectable ti ters of xenoreactive antibodies, which began to reappear by postoperative d ay 2, where xenografts showed histologic stigmata of acute (humoral and cel lular-mediated) rejection that evolved to a complete xenograft necrose at d eath, Group 4 xenografts showed scattered features of acute rejection 5 +/- 1 days after the operation. Conclusions: Pig left lung xenografts can prov ide prolonged and complete respiratory support after depletion of goat xeno reactive antibodies, but they ultimately necrose once recipient xenoreactiv e antibodies return to pretransplantation values.