A closer look at chronic rejection in the murine model of orthotopic lung transplantation

Abstract

Long-term survival after lung transplantation (LTx) is limited by chronic rejection of which two clinical phenotypes have been defined: bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). The pathophysiology of chronic rejection remains unclear and consequently prognosis is poor. Therefore a preclinical model is essential to investigate its elusive pathology. The murine orthotopic LTx in a major antigen-mismatch combination is of greatest clinical relevance since it mimics the LTx procedure and recipients require daily immunosuppression. However, until now this model is not used consistently. Hence the aim is to provide an in-depth investigation of the orthotopic LTx mouse model in the context of chronic rejection. Innovatively, a longitudinal non-invasive follow-up is implemented using in vivo µCT. We identified that murine orthotopic LTx demonstrated histopathological features comparable to RAS. In addition, µCT scans showed a progressive worsening graft, with a decreased total lung volume and an increased mean lung density. However, we also observed necrotic lungs and complete consolidation on µCT, indicating a too severe phenotype of chronic rejection. Hence the immunosuppressive scheme was adjusted and serial histological assessment was performed. Initial findings show that a higher immunosuppression and shorter follow-up might be better resembling the clinical situation. Nevertheless, the model needs optimization but can become a robust animal model for translational purposes.