A B cell–dependent pathway drives chronic lung allograft rejection after ischemia–reperfusion injury in mice

Chronic lung allograft dysfunction (CLAD) limits long‐term survival after lung transplant (LT). Ischemia–reperfusion injury (IRI) promotes chronic rejection (CR) and CLAD, but the underlying mechanisms are not well understood. To examine mechanisms linking IRI to CR, a mouse orthotopic LT model using a minor alloantigen strain mismatch (C57BL/10 [B10, H‐2b] → C57BL/6 [B6, H‐2b]) and isograft controls (B6→B6) was used with antecedent minimal or prolonged graft storage. The latter resulted in IRI with subsequent airway and parenchymal fibrosis in prolonged storage allografts but not isografts. This pattern of CR after IRI was associated with the formation of B cell–rich tertiary lymphoid organs within the grafts and circulating autoantibodies. These processes were attenuated by B cell depletion, despite preservation of allograft T cell content. Our observations suggest that IRI may promote B cell recruitment that drives CR after LT. These observations have implications for the mechanisms leading to CLAD after LT. A critical role for B cells in the development of late allograft fibrosis after ischemia–reperfusion injury is revealed using a mouse orthotopic lung transplant model.