Lymphoid neogenesis in murine cardiac allografts undergoing chronic rejection

Lymphoid neogenesis is the process by which ectopic lymphoid accumulations that resemble lymph nodes arise in nonlymphoid tissues. Such lymphoid accumulations, known as tertiary lymphoid organs (TLO), are observed in chronic autoimmunity and they propagate immune pathology by setting up local antigen presenting sites. Whether lymphoid neogenesis occurs in transplanted organs and contributes to rejection is not well understood. To begin to address this question, we retrospectively analyzed 319 murine cardiac allografts for microscopic evidence of lymph-node-like structures. We found 78 allografts that had either classical TLO, characterized by discrete T- and B-cell zones and high endothelial venules (HEV) expressing peripheral node addressin (PNAd) (n = 34), or PNAd⁺ HEV without organized lymphoid accumulations (n = 44). These changes were present in both short- and long-lived allografts and were invariably associated with rejection. Importantly, they occurred in 78% of allografts undergoing chronic rejection (n = 85) but in only 7% of allografts undergoing primarily acute rejection (n = 184). These findings indicate that, like autoimmunity, alloimmunity is associated with lymphoid neogenesis in the target organ and suggest a role for local T-cell activation in chronic allograft rejection.