Preconditioning donors with corticosteroids improves the early lung graft immunity

Isabelle Schwartz-cornil^1*Florentina Pascale^1,2Jouneau Luc¹Maxime Huriet^1,2Jérôme Estephan^1,2Mickael Bourge³Christophe Richard⁴Valérie GELIN⁴Claudia Bevilacqua⁵Julie Rivière^5,6Thien-Phong Vu Manh⁷Maxime Djebbour¹Antoine Premachandra¹Carla Gouin¹Julien De Wolf^1,2Chloé Mimbimi²Antoine Magnan^1,2Antoine Roux^1,2Stanislas Grassin-Delyle^8,9Philippe Devillier^1,10,9Delphyne Descamps¹Nicolas Bertho¹¹Sébastien Jacqmin¹²Morgan Le Guen¹²Edouard Sage^1,2Matthieu Glorion^1,2

• ¹UMR0892 Virologie moléculaire et immunologie (VIM), Jouy En Josas, France
• ²Hopital Foch, Suresnes, France
• ³Cytometry / Electronic Microscopy / Light Microscopy Facility, Imagerie-Gif, Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette, France
• ⁴Université Paris-Saclay, UVSQ, INRAE, BREED, Jouy-en-Josas, France
• ⁵Université Paris-Saclay, AgroParisTech, INRAE, GABI, Jouy en Josas, France
• ⁶Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy en Josas, France
• ⁷Aix Marseille University, CNRS, Inserm, CIML Centre d'Immunologie de Marseille-Luminy, Turing Center for Living Systems, Marseille, France
• ⁸Université Paris-Saclay, UVSQ, INSERM, Infection et inflammation, U1173, Département de Biotechnologie de La Santé, Montigny-le-Bretonneux, France
• ⁹Exhalomics®, Hôpital Foch, Suresnes, France
• ¹⁰Department of Pharmacology, Foch Hospital, Suresnes, France
• ¹¹Oniris, INRAE, BIOEPAR, Nantes, France
• ¹²Hopital Foch Service d'Anesthesie, Suresnes, France

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: Donor preconditioning - compared to recipient's treatment alone - reduced the presence of CD3pos 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.