Orthotopic tracheal transplantation using human bronchus: an original xenotransplant model of obliterative airway disorder

Abstract

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 Day 7 (BN , n = 6; RNU , n = 7) or Day 28 (BN , n = 6; RNU , 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 was observed in the BN group on Day 28. 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). Xenoreactive antibodies were significantly higher at Day 7 (IgM) and Day 28 (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 highly 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.

Granulomatous Inflammation in ANCA-Associated Vasculitis

“…S100A4 + cells (red, ( C )) and Vimentin + cells (reddish brown, ( D )) invading bone ( b ) in nasal tissue of GPA (serial staining), presumably fibroblasts. Immunohistochemistry for S100A4 in nasal tissue of GPA ( n = 3) was performed as described previously [ 164 ]. The upper respiratory tract tissue samples of GPA were characterized in previous studies [ 22 , 76 ].…”

Humanization of Immunodeficient Animals for the Modeling of Transplantation, Graft Versus Host Disease, and Regenerative Medicine

“…Nude Foxn1 RNU rats have been transplanted with a variety of human stem cells or organs in different models of transplantation and regenerative medicine, including models of intestinal transplantation, 130 bronchus grafts, 131 nephropathy, 132 liver, 133 , 134 cardiac infarct, 135 - 137 bone and chondrocyte healing and regeneration, 138 - 142 rotator cuff lesions, 143 , 144 tendon lesions, 145 , 146 brain or spinal trauma, 147 - 155 urethral dysfunction, 156 , 157 retinal degeneration, 158 - 162 in vivo differentiation of ES cell-derived pancreatic beta cells, 163 multiciliated airway cells for the generation of an artificial trachea, 164 and periodontal tissues 165 (Table 2 ).…”

New Targets for the Prevention of Chronic Rejection after Thoracic Organ Transplantation

“…Similar to heart grafts, transplanted lungs may develop chronic rejection which clinically manifests as fibroproliferative changes of the bronchial walls and is called chronic lung allograft dysfunction (CLAD), obliterative airway disease, obliterative bronchiolitis, 58 or bronchiolitis obliterans syndrome. 59 Chronic rejection following lung transplantation is even more common than after heart transplantation and accordingly responsible for a higher rate of posttransplantation deaths. 59 About 50% of patients developed CLAD within 5 years after transplantation and even 76% within 10 years.…”

“…59 Chronic rejection following lung transplantation is even more common than after heart transplantation and accordingly responsible for a higher rate of posttransplantation deaths. 59 About 50% of patients developed CLAD within 5 years after transplantation and even 76% within 10 years. In up to 23% of patients surviving more than 10 years after transplantation, CLAD was the cause of death.…”

“…To facilitate the detection of CLAD, different molecules were already identified as possible biomarkers. [68][69][70] Guihaire et al 59 propose another marker molecule for CLAD development. They analyzed the expression of the protein S100A4, which is primarily expressed by fibroblasts and immune cells, in a rat model of trachea transplantation.…”