Different Chronic Allograft Pathology Lesions in Two Orthotopic Lung Transplant Rat Strain Combinations

Purpose Chronic lung allograft dysfunction (CLAD) remains the major obstacle to long-term survival after lung transplantation. Two different phenotypes have recently been described. About 80% of patients have primarily obstructive lung disease associated with obliterative bronchiolitis, airway fibrosis with intraluminal narrowing (OB-CLAD) while a smaller subset has lung restriction with hypoxemia and parenchymal fibrosis (R-CLAD). Preclinical modeling is essential to better analyze the pathophysiological processes leading to CLAD development. Lung allografts from a large cohort of two different rat strain combinations orthotopically transplanted in the last decade were re-evaluated. Methods From 2007 to 2017 127 rats were transplanted in our centre: 55 Lewis (Lew; RT-1l) into Fisher 344 (F344; RT-1v) (Group 1, G1) and 72 Brown-Norway (BN; RT1n) into Lew (Group 2, G2). Chronic rejection was detected in 39 cases, 18 G1 and 21 G2 rats, respectively, at a mean time of 61 and 17 days, respectively. Several pathological lesions (airway, pleural and vascular fibrosis, airway obliteration, endothelialitis, lymphoid aggregates, epithelial hyperplasia and flattening) were graded following a recent proposed grading system for animal model CLAD (Martinu et al, 2019, AJT). Results An end stage lung remodelling was detected in 33% of G1 and 48% of G2 models. A vanishing obliterative bronchiolitis (end stage OB-CLAD) was observed in 33% and 20% of G1 and G2 rats, respectively, while signs of fibrosis/fibroelastosis (end stage R-CLAD) were detected in 67% and 80% of G1 and G2 rats, respectively. Acute fibrinous and organizing pneumonia (AFOP) was present in 37.5% of G2 strains and never observed in G1 animals. Interestingly, G2 rats showed higher endothelialitis, vascular fibrosis and lower lymphoid aggregates than G1 strain (p=0.005, p=0.01, p=0.03, respectively). A combination score of highly suggestive R-CLAD lesions (parenchymal, pleural, vascular fibrosis and endothelialitis) was more frequently detected in G2 rats (p=0.03). Conclusion CLAD associated lesions in lung rat allografts mimic those observed in humans. The earlier R-CLAD developed in G2 may be related to a higher degree of mismatch in this strain combination. These animal models could allow future mechanistic studies to better understand CLAD pathogenesis.