Primary Graft Dysfunction Following Lung Transplantation is Associated with Increased In Vivo T Cell Alloreactivity: Evidence from a Humanized Mouse Model

Abstract

<h3>Purpose</h3> Primary graft dysfunction (PGD) is one of the leading causes 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. <h3>Methods</h3> The pericardio-phrenic artery obtained from human donor lungs was implanted into the aorta of NOD/Rag-/-/IL-2rγc-/- mice reconstituted with either naive or primed allogeneic peripheral blood mononuclear cells (PBMC), that were obtained from the respective lung recipient either before or 21 days after transplantation. Parallel to the previously described experimental groups, there was another group. Here, T regs were enriched and additionally injected with the PBMC. Exactly as mentioned before, on day 0 and day 21. PGD was defined according to the 2017 ISHLT Guidelines. <h3>Results</h3> Histological assessment after 28 days showed significantly more intimal hyperplasia of arteries in mice reconstituted with PBMC from patients with PGD (24 hours after transplantation; score 2 or 3) compared to patients without PGD (score 0 or 1). The attached figure shows the measured occlusion in the individual groups. Enriching of PBMC with CD4+CD25high regulatory T cells (Treg) subpopulation, 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 serum concentrations IFN-γ (PGD: 1129,9 conc. Pg/ml vs noPGD: 577,24 conc. Pg/ml), a pro-inflammatory TH1 signature cytokine. <h3>Conclusion</h3> 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, which suggests a potential target for future early interventions in lung transplantation.