Orthotopic lung transplantation in mice: Development of a bronchiolitis obliterans model

Introduction: Bronchiolitis obliterans syndrome causes an irreversible pathology of the transplanted lung and remains the major reason for late mortality after lung transplantation. There is no effective therapy for BOS and good animal models for the disease are scarce. Only recently, the first orthotopic lung transplantation model in mice was developed. In our study, we have focused on inducing BOS using a minor histocompatibility antigen mismatched strain combination in this murine model.

Materials: Orthotopic lung transplantation in mice was done using a modification of the techniques described by Okazaki and Jungrathmayr. Experimental design included 4 groups. Group-I (isogenic) – C57BL/6 to C57BL/6, II- (immundeficient) – NRG to NRG, III – (minor Ag) – C57BL/6 to C57BL/10 and IV- (minor Ag) C57BL/10 to C57BL/6. The transplanted lungs were harvested after 28 days. Read out parameters involved clinical assessment, X-ray, micro CT, MRT and histology.

Results: 90% of experimental animals survived to 28 days. Group I and group II animals did not show signs of acute or chronic rejection in transplanted lungs. Interesting results were observed in the two groups transplanted over minor antigen barriers. No significant differences in between these two groups were seen, with both showing signs of ongoing BOS as well as signs of acute cellular rejection. Tomographic assessment showed bronchial tree remodelling as well as alveolar infiltration. Histological changes included mononuclear cell infiltration, alveolar tissue degradation and interstitial inflammation. Bronchial lesions were pronounced in form of interstitial inflammation and mostly fibrotic changes varying from fibrotic plug to complete obliteration. Aberrant remodelling of epithelial, vascular and bronchial tissue was inhomogeneous between animals. Overall, an advanced state of BOS in conjunction with acute cellular rejection was induced.

Discussion: Our model allowed us to develop bronchial damage similar to BOS in 28 days after transplantation. Minor Ag mismatch proved to be effective in reproducing these severe bronchial lesions after lung transplantation. However, manifestation of acute rejection patterns was still impairing our end assessment. The next step in our study will be to refine the BOS model by counteracting acute rejection. This could potentially be achieved by administering subtherapeutic doses of immunosupression in the minor antigen mismatched strain combination.