Lung rehabilitation using xenogeneic cross-circulation does not lead to hyperacute rejection in a human lung transplantation model

Abstract

Background: Access to life-saving lung transplantation remains limited by a shortage of donor organs. We have previously described rehabilitation of discarded human donor lungs to a quality suitable for transplantation using cross-circulation of whole blood between xeno-support swine and human lungs. However, the immunologic implications of transplanting rehabilitated lungs remain unknown.

Methods: Human donor lungs declined for clinical transplantation (N = 5) and underwent xenogeneic cross-circulation (XC) for up to 12 hours. To model subsequent human transplantation, lungs were re-exposed to autologous human whole blood via normothermic ex vivo machine perfusion for up to 6 hours. Upon human blood re-exposure (HBR), lungs were evaluated for evidence of hyperacute rejection (HAR) through physiologic assessments and tissue analyses including histology, immunostaining, and flow cytometry.

Results: Upon HBR, lungs showed no significant change in physiologic function relative to the end of cross-circulation (PaO₂/FiO₂: p = 0.41; vascular resistance: p = 0.27; dynamic compliance: p = 0.24) and histologic features of HAR were absent in all lungs. Despite pulmonary deposition of porcine IgG during cross-circulation, HBR resulted in decreased complement deposition (p = 0.019) with no change in membrane attack complex formation (p = 0.65) or apoptotic signaling (p = 0.93). Endothelial integrity was maintained after HBR with preservation of microvascular tight junctions, decreasing endothelial injury marker p-selectin (p = 0.34), and intact vascular response to alpha-adrenergic stimulation.

Conclusions: Our findings indicate that transient exposure of human donor lungs to XC does not result in HAR upon simulated human transplantation, representing an important step toward clinical translation of this donor organ rehabilitation platform.

Keywords: human lung transplantation model; lung rehabilitation; lung transplantation; transplant immunology; xenogeneic cross-circulation.