B6 Donor Lungs Develop Chronic Lung Allograft Dysfunction–like Pathology Across Histocompatibility Mismatches in Murine Lung Transplantation

Background. Chronic lung allograft dysfunction (CLAD) remains a major barrier to long-term survival after lung transplantation. Murine models are essential for mechanistic studies, but the influence of donor-recipient strain direction and histocompatibility mismatch on chronic pathology is not fully defined. We evaluated the reproducibility of B6-background donor lungs across reciprocal strain combinations as a practical experimental platform. Methods. Orthotopic left lung transplantation was performed using major-mismatched (C57BL/6 [B6]↔BALB/c) and minor-mismatched (B6↔C57BL/10 [B10]) combinations. Major-mismatched recipients received costimulatory blockades (anti-CD40L/cytotoxic T-lymphocyte–associated protein 4 Ig); minor-mismatched pairs received no immunosuppression. Grafts were procured on day 28. Chronic injury was quantified using standardized histological scoring for airway, parenchymal, and pleural compartments. Lung function was assessed using the FlexiVent system with right hilar clamping. Results. CLAD-like airway and fibrotic lesions developed across all combinations, irrespective of donor-recipient direction. B6 donor lungs reproducibly exhibited chronic pathology comparable with other strains. Notably, the incidence of obliterative bronchiolitis was higher in minor-mismatched groups (B10→B6: 54.5%; B6→B10: 38.5%) compared with major-mismatched groups (BALB/c→B6: 27.3%; B6→BALB/c: 36.4%). Histological severity significantly correlated with impaired lung compliance and increased airflow resistance, supporting the functional relevance of the observed structural injury. Conclusions. Reciprocal murine lung transplantation reveals that CLAD-like pathology develops irrespective of donor-recipient direction, with mismatch degree influencing the qualitative distribution of chronic injury. These findings validate B6-background donor lungs as a versatile platform for interrogating donor-intrinsic immune and stromal mechanisms of chronic rejection, and for hypothesis-driven testing of donor-targeted interventions using genetically modified strains.