Primary Graft Dysfunction following Lung Transplantation Is Associated with Increased In Vivo T-Cell Alloreactivity

Background: Primary graft dysfunction (PGD) is the leading cause of early mortality following lung transplantation (LTx). Here, we investigated the correlation between PGD early after lung transplantation and the subsequent development of transplant atherosclerosis (TA) in a humanized mouse model.

Method: The pericardiophrenic artery obtained from human donor lungs was implanted into the aorta of NOD/Rag−/−/IL-2rgc−/− mice reconstituted with either naive or primed allogeneic peripheral blood mononuclear cells (PBMC). These were obtained from the respective lung recipient either before or 21 days after transplantation.

Results: Histological assessment after 28 days showed significantly more intimal hyperplasia of arteries in mice reconstituted with PBMC from patients with PGD (score 2 or 3) compared with patients without PGD (score 0 or 1). Enriching of CD4 + CD25 high regulatory T cells (Treg) in PBMC suppressed the development of TA in both PGD groups. TA was similarly suppressed by enriching of naive or alloantigen-primed Treg. Mice transplanted with arteries from donors undergoing PGD score 2 or 3 developed higher CXCL10 (IP-10) serum concentrations.

Conclusion: We conclude that both donor tissue inflammation and recipient T cell responses contribute to PGD, eventually triggering rejection. This inflammatory response can be suppressed by early supplementation with Treg cells, indicating a potential target for future early interventions in lung transplantation.

Publication History

Article published online:
03 February 2022