Radiological and Pathological Findings in a Minor-mismatch Mouse Orthotopic Lung Transplant Model under Immunosuppression

Abstract

Background: Mouse orthotopic lung transplantation (MOLTx) models are extremely useful. However, there are only few studies on non-invasive monitoring methods for lung rejection in these models. Additionally, a model of chronic rejection has so far been difficult to reproduce consistently with MOLTx.

Objective: To determine if CT scan of the lung graft can be considered a useful noninvasive monitoring method of evaluation of graft rejection in an animal lung transplantation model.

Methods: Left MOLTx was performed from B10 donors into B6 recipients (from B6 donors for syngeneic controls). Following transplantation, 3 different doses of cyclosporine—5, 15, and 25 mg/kg daily—were administered in the first week to suppress acute rejection. Positive controls did not receive cyclosporine. 8 weeks after transplantation, CT and histological rejection grading were performed.

Results: The negative controls did not show any inflammation. Positive controls revealed moderate acute rejection (A3). A3 was also detected in the 5-mg/kg group (100%). The 15-mg/kg group (n=7) demonstrated A3 in 4 mice and mild acute rejection (A2) in the remaining 3 mice. In this group, 4 mice had bronchiolitis obliterans (BO; C1, 57%). The 25-mg/kg group (n=3) showed A3 changes in 1 and A2 in 2 mice. On CT scan, lungs without BO (C0) had radiodensities of ‑278.1±110.7 Hounsfield units (HU). C1 lungs had ground-glass opacity or atelectasis with ‑83.4±46.8 HU (C0 vs. C1, p<0.001). On grouping with A2 or A3 in C0, significant differences were detected: ‑375.3±41.2 vs. ‑185.0±38.4 HU (A2+C0 vs. A3+C0, respectively), p=0.01.

Conclusion: BO can be modeled using this MOLTx model by administration of subtherapeutic doses of cyclosporine. CT scans are a valid tool for monitoring of rejection following MOLTx.