Orthotopic Tracheal Transplantation using Human Bronchus: an Original Xenotransplant Model of Obliterative Airway Disorder

Bronchiolitis obliterans syndrome (BOS) is a main cause of allograft dysfunction and mortality after lung transplantation (LTx). A better understanding of BOS pathogenesis is needed to overcome this treatment-refractory complication. Orthotopic tracheal transplantation using human bronchus was performed in Brown Norway (BN) and nude (RNU) rats. Allografts were recovered in both strains at Day7 (BN7 , n=6; RNU7 , n=7) or Day28 (BN28 , n=6; RNU28 , n=6). Immune response of the host against the bronchial graft was assessed. Human samples from BOS patients were used to compare with the histological features of the animal model. Obstruction of the allograft lumen associated with significant infiltration of CD3+ and CD68+ cells were observed in the BN group on Day28. Immune response from type 1 T-helper cells against the tracheal xenograft was higher in BN animals compared to nude animals on Days 7 and 28 (P<0.001 and P=0.035). Xeno-reactive antibodies were significantly higher at Day7 (IgM) and Day28 (IgG) in the BN group compared to RNU (respectively 37.6 ± 6.5 vs. 5.8 ± 0.7 mean fluorescence, P=0.039; and 22.4 ± 3.8 vs. 6.9 ± 1.6 mean fluorescence, P=0.011). Immunocompetent animals showed a higher infiltration of S100A4+ cells inside the bronchial wall after 28 days, associated with cartilage damage ranging from invasion to complete destruction. In vitro expression of S100A4 by human fibroblasts was higher when stimulated by mononuclear cells (MNCs) from BN rats than from RNU (2.9 ± 0.1 vs. 2.4 ± 0.1 mean fluorescence intensity, P=0.005). Similarly, S100A4 was higher expressed in response to human MNCs compared to stimulation by T-cell depleted human MNCs (4.3 ± 0.2 vs. 2.7 ± 0.1 mean fluorescence intensity, P<0.001). Obliterative bronchiolitis has been induced in a new xenotransplant model in which chronic airway obstruction was associated with immune activation against the xenograft. Cartilage infiltration by S100A4+ cells might be stimulated by T-cells. This article is protected by copyright. All rights reserved.