Abstract
The lack of a robust mouse model for lung transplantation severely impairs our understanding of the mechanisms of chronic lung allograft dysfunction (CLAD). While murine models of acute or progressive allograft rejection, based on full donor/recipient mismatch, have been described, their routine use is limited because of a lack of robust features of bronchiolar obliteration. Based on the evidence that T cells from CLAD patients recognize mismatched HLA molecules in an indirect fashion, we here sought to establish a mouse model of chronic lung allograft rejection based on indirect allorecognition of donor tissue.
Left lungs from C57BL/6J (syngeneic group) or mice on a C57BL/6J background carrying a single human HLA-A2.1 molecule (allogeneic group) were orthotopically transplanted into C57BL/6J recipients and analyzed one month after orthotopic single lung transplantation.
Lung grafts obtained from the syngeneic group appeared normal, as assessed by dark-field imaging and histological analysis. In contrast, the allogeneic group presented significantly less scattering in dark-field imaging, strongly suggesting a partial loss of graft lung function. Histological analysis demonstrated injury and altered cellular composition of the bronchiolar epithelium. The subepithelial peribronchiolar compartment was infiltrated by inflammatory cells and subepithelial fibrosis was evident in allogeneic transplant recipients.
Thus, a single indirect allorecognition-triggering mismatch provokes a chronic rejection of the graft. Epithelial changes resemble those of CLAD patients and are likely to represent early processes inducing long-term bronchiolar obliteration.
- Copyright ©the authors 2016
