Preconditioning donors with corticosteroids improves early lung graft immunity

Background: Preclinical studies have recently revealed the critical role of innate immunity in determining lung transplantation outcomes. Although the International Society for Heart and Lung Transplantation recommends high-dose corticosteroid administration to donors, this practice is inconsistently applied worldwide. Investigating its impact on the donor lung's innate immune response - an unexplored area - could provide valuable evidence to support adoption of donor preconditioning with corticosteroids, beyond their traditional administration to recipients. Method: We used a cross-circulatory pig platform that consists of a donor lung placed extracorporeally and connected to the circulation of a recipient pig whose leukocytes are fluorescently labeled. Results: T-cells in the graft from both the donor and recipient, and enhanced the anti-inflammatory profile of alveolar macrophages, at least during the first 10 hours of donor-recipient interaction. The alveolar macrophages isolated from corticosteroid-preconditioned pig lungs exhibited decreased gene expression of T-cell-attracting chemokines during the 10-hour reperfusion period, correlating with the reduced T-cell infiltration. Similarly, human lung macrophages showed lower expression of these T-cell-attracting chemokines and higher anti-inflammatory profiles with corticosteroid treatment. Conclusion: Our results show that the early immune status of lung grafts is improved by treating donors with corticosteroids through macrophage-targeted mechanisms. This finding provides an immunological rationale for expanding the implementation of donor preconditioning with corticosteroids.