Fibrosis of Chronic Lung Allograft Dysfunction after Orthotopic Lung Transplantation is Prevented in the Absence of Secondary Lymphoid Organs in a Mouse Model

Purpose It was reported that acute lung allograft rejection occurred without secondary lymphoid organs (SLOs) in a mouse allogenic lung transplantation model. The objective of this study was to investigate the role of SLOs in chronic lung allograft dysfunction (CLAD) after allogenic mouse lung transplantation using splenectomized alymphoplastic (aly/aly) mice as SLOs-deficient recipient. Methods Left lung of BALB/c mouse was transplanted into C57BL/6J (B6) or aly/aly mouse with B6 background. Low-dose cyclosporine (10 mg/kg, 3 times/week) and methylprednisolone (1.6 mg/kg, 3 times/week) were given in all the recipient mice until sacrifice. The recipient mice were sacrificed at day 15 (D15, n=4, each group) or day 30 (D30, n=5, each group) to evaluate histology. Results Allograft in B6 mice showed A2-3 rejection on D15 and A2-3 rejection with severe peri-airway and peri-vascular fibrosis on D30. On the contrary, allograft in aly/aly mouse showed A1-2 rejection on D15 and D30 without fibrosis (Figure 1). Quantification of peri-airway fibrosis thickness demonstrated significantly less fibrotic change in aly/aly mice than B6 mice on D30 (p = 0.012) (Figure 2). The A grade rejection score was significantly low on D30 in aly/aly mice (median A1, range A1-A2) than B6 mice (median A3, range A2-A3) (p = 0.015). Conclusion Fibrotic change with cellular rejection did not occur in the absence of SLOs in a mouse model of CLAD induced by inadequate immunosuppression, which may provide a platform for novel strategy to prevent CLAD. It was reported that acute lung allograft rejection occurred without secondary lymphoid organs (SLOs) in a mouse allogenic lung transplantation model. The objective of this study was to investigate the role of SLOs in chronic lung allograft dysfunction (CLAD) after allogenic mouse lung transplantation using splenectomized alymphoplastic (aly/aly) mice as SLOs-deficient recipient. Left lung of BALB/c mouse was transplanted into C57BL/6J (B6) or aly/aly mouse with B6 background. Low-dose cyclosporine (10 mg/kg, 3 times/week) and methylprednisolone (1.6 mg/kg, 3 times/week) were given in all the recipient mice until sacrifice. The recipient mice were sacrificed at day 15 (D15, n=4, each group) or day 30 (D30, n=5, each group) to evaluate histology. Allograft in B6 mice showed A2-3 rejection on D15 and A2-3 rejection with severe peri-airway and peri-vascular fibrosis on D30. On the contrary, allograft in aly/aly mouse showed A1-2 rejection on D15 and D30 without fibrosis (Figure 1). Quantification of peri-airway fibrosis thickness demonstrated significantly less fibrotic change in aly/aly mice than B6 mice on D30 (p = 0.012) (Figure 2). The A grade rejection score was significantly low on D30 in aly/aly mice (median A1, range A1-A2) than B6 mice (median A3, range A2-A3) (p = 0.015). Fibrotic change with cellular rejection did not occur in the absence of SLOs in a mouse model of CLAD induced by inadequate immunosuppression, which may provide a platform for novel strategy to prevent CLAD.