Tackling the early lung graft immunity by preconditioning donors with corticosteroids
Though lung transplantation (LT) is increasingly used to treat end-stage lung diseases, the clinical outcomes are disappointing, underscoring the need for novel therapeutic strategies. Preclinical studies revealed the critical role of innate immunity in LT outcomes. While corticosteroid boluses are routinely given to recipients, we hypothesized that donor preconditioning with corticosteroid could improve early immune parameters, in the context of ongoing clinical trials exploring various preconditioning approaches. We used a cross-circulatory pig platform that consists in a donor lung placed extracorporeally and connected to the circulation of a recipient pig whose leukocytes are fluorescently labelled. Donor preconditioning reduced the presence of CD3pos T-cell in the graft from both the donor and recipient, and enhanced the anti-inflammatory profile of alveolar macrophages, at least during 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 upon corticosteroid treatment. Thus, the early immune status of lung grafts is improved by donor preconditioning with corticosteroids through macrophage-targeted mechanisms, holding promises for enhanced clinical outcomes. Overall design: scRNA-seq of MHC class II-positive cells from one pig lung