Chronic Rejection Pathology after Orthotopic Lung Transplantation in Mice: The Development of a Murine BOS Model and Its Drawbacks

Abstract

Almost all animal models for chronic rejection (CR) after lung transplantation (LTx) fail to resemble the human situation. It was our attempt to develop a representative model of CR in mice. Orthotopic LTx was performed in allografts receiving daily immunosuppression with steroids and cyclosporine. Controls included isografts and mice only undergoing thoracotomy (SHAM). Allografts were sacrificed 2, 4, 6, 8, 10 or 12 weeks after LTx. Pulmonary function was measured repeatedly in the 12w allografts, isografts and SHAM mice. Histologically, all allografts demonstrated acute rejection (AR) around the blood vessels and airways two weeks after LTx. This decreased to 50–75% up to 10 weeks and was absent after 12 weeks. Obliterative bronchiolitis (OB) lesions were observed in 25–50% of the mice from 4–12 weeks. Isografts and lungs of SHAM mice were normal after 12 weeks. Pulmonary function measurements showed a decline in FEV0.1, TLC and compliance in the allografts postoperatively (2 weeks) with a slow recovery over time. After this initial decline, lung function of allografts increased more than in isografts and SHAM mice indicating that pulmonary function measurement is not a good tool to diagnose CR in a mouse. We conclude that a true model for CR, with clear OB lesions in about one third of the animals, but without a decline in lung function, is possible. This model is an important step forward in the development of an ideal model for CR which will open new perspectives in unraveling CR pathogenesis and exploring new treatment options.

CD8+IL-17+T Cells Mediate Neutrophilic Airway Obliteration in T-bet–Deficient Mouse Lung Allograft Recipients

“…In contrast, a recent study in this model showed obliterative airway lesions in minor histocompatibility mismatched transplants that were significantly reduced after neutralization of IL-17A (8). Also notable was a recent report of similar airway lesions in fully MHC-mismatched transplants treated with conventional immunosuppression, including cyclosporine A and corticosteroids, although cytokine responses were not evaluated in this study (9). Although IFN-g-mediated type 1 responses have been demonstrated in ACR in multiple experimental transplant models, including the mouse orthotopic lung transplant model, these responses have also been shown to be dispensable for rejection.…”

“…Therefore, this molecular state could be relevant to the clinical field of lung transplant. In fact, a recent study showed the development of OB lesions in mouse recipients of orthotopic lung transplant that were treated with calcineurin inhibitors and steroids, whereas these lesions have not been previously described in the untreated, fully MHC-mismatched mouse model (9), suggesting a possible role of immunosuppression effects in the development of these lesions. Moreover, we believe that understanding the downstream, pathologic effects of the CD8 (36).…”

“…It is therefore possible that the absence of T-bet in innate cells in our model contributes in a meaningful way to the allograft rejection pathology and T cell effector responses we see in these T-bet 2/2 recipients. Finally, in our studies we did not treat allograft recipients with conventional immunosuppression to evaluate the effects of more targeted immunomodulation on allograft rejection and allo-specific responses; however, a recent study using this approach raises interesting and unanswered questions regarding the role of these therapies in obliterative airways disease development (9).…”

Spleen Tyrosine Kinase Modulates Fibrous Airway Obliteration and Associated Lymphoid Neogenesis After Transplantation

“…Although mouse orthotopic lung transplant models are increasingly used, the consistency of reproducing BOS and chronic rejection is concerning (38,39). To improve the tracheal transplant model to better recapitulate the human setting of OB, we adapted the traditional subcutaneous approach by conducting IPTT, which places the allograft into a pulmonary milieu.…”

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

“…However, these airway fibrotic lesions were noted in only 50% of the transplanted mice and were limited to a small number of airways in the allografts. Use of immunosuppression (cyclosporine + steroids) to prolong graft life in MHC mismatch (BALB/c→C57BL/6) has also allowed for investigation of the development of OB pathology (119). This model only generates OB-like lesions in 25%-50% of the mice, with many mice demonstrating no evidence of OB or regaining normal histology after 12 weeks.…”