HLA-Silenced Cell Therapy Enhances Donor Lung Recovery and Mitigates Primary Graft Dysfunction in a Porcine Transplant Model

Introduction: Lung transplantation remains the only definitive treatment for patients with end-stage lung disease, but its impact is limited by the shortage of transplantable donor lungs. Aspiration-induced injury is a frequent cause of donor lung discard and increases the risk of primary graft dysfunction (PGD) after transplantation. Mesenchymal stromal cells (MSCs) have shown potential to improve function in injured donor lungs during ex vivo lung perfusion (EVLP); however, allogeneic MSCs may still be recognized by the host immune system through HLA expression. We therefore examined whether HLA-silenced MSCs could improve recovery of injured donor lungs in this setting.
Methods: Aspiration-induced lung injury was established in a clinically relevant porcine model by intratracheal instillation of gastric contents over 6 hours. Injured lungs then underwent 4 hours of EVLP with HLA class I/II-silenced bone marrow-derived MSCs, unmodified bone marrow-derived MSCs, or placebo treatment (n=4/group). Following EVLP, left lung transplantation was performed into healthy recipient pigs. Treatment was first delivered to the graft during EVLP and then repeated in the recipient after transplantation. Recipients were monitored for 3 days, including isolated graft assessment for an additional 4 hours after right pneumonectomy. PGD was evaluated by PaO₂/FiO₂ ratio and chest radiography. Histopathology and multiplex immunofluorescence were used to assess tissue injury and treatment-associated effects.
Results: PGD was not observed in recipients receiving MSC-treated grafts, whereas severe PGD was common in the placebo group. In parallel, both MSC-treated groups showed improved lung compliance and lower pulmonary vascular resistance than placebo. On histologic assessment, placebo-treated grafts showed typical features of acute lung injury, including edema, thickened alveolar septa, inflammatory cell infiltration, and increased apoptosis. In contrast, MSC-treated lungs displayed better-preserved architecture with less edema, inflammation, and apoptosis. The strongest overall effect was observed in the HLA-silenced MSC group, which showed the lowest degree of histologic injury.
Conclusion: HLA-silenced MSC treatment of the graft during EVLP, followed by repeat treatment after transplantation, improved recovery of aspiration-injured donor lungs and reduced early graft dysfunction in this porcine model. These findings support further investigation of HLA-silenced MSC therapy for donor lung restoration and treatment in lung transplantation.