Fibrotic progression from acute cellular rejection is dependent on secondary lymphoid organs in a mouse model of chronic lung allograft dysfunction

Abstract

Chronic lung allograft dysfunction (CLAD) remains one of the major limitations to long term survival after lung transplantation. We modified a murine model of CLAD and transplanted left lungs from BALB/c donors into B6 recipients that were treated with intermittent cyclosporine and methylprednisolone postoperatively. In this model, the lung allograft developed acute cellular rejection on day 15 (D15) which, by D30 after transplantation, progressed to severe pleural and peribronchovascular fibrosis, reminiscent of changes observed in restrictive allograft syndrome (RAS). Lung transplantation into splenectomized B6 alymphoplastic (aly/aly) or splenectomized B6 lymphotoxin-β receptor (LTβR)-deficient mice demonstrated that recipient secondary lymphoid organs (SLOs), such as spleen and lymph nodes, are necessary for progression from acute cellular rejection to allograft fibrosis in this model. Our work uncovered a critical role for recipient SLOs in the development of CLAD after pulmonary transplantation and may provide mechanistic insights into the pathogenesis of this complication.