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J Thorac Cardiovasc Surg 1997;114:315-325
© 1997 Mosby, Inc.

CARDIAC AND PULMONARY REPLACEMENT

EX VIVO LUNG MODEL OF PIG-TO-HUMAN HYPERACUTE XENOGRAFT REJECTION

Supported by the Concerted Action (No. 3026PL950004) of the Immunology Biotechnology Program from the European Union and an East-West INSERM contract.

Received for publication Dec. 16, 1996; revisions requested Feb. 14, 1997; revisions received Feb. 28, 1997; accepted for publication April 9, 1997. Address for reprints: Paolo Macchiarini, MD, Department of Thoracic and Vascular Surgery, and Heart-Lung Transplantation, Hôpital Marie-Lannelongue (Paris-Sud University), 133, Avenue de la Resistance, 92350 Le Plessis Robinson, France.

Abstract

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-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 (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.

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