Cytokine Expression and Alloreactivity in a Humanized Mouse Transplant Arteriosclerosis Model Reflects Primary Graft Dysfunction in Lung Transplant Recipients

Purpose An important cause of early mortality after lung transplantation is primary graft dysfunction (PGD). In a humanized mouse model, we studied the impact of the baseline condition of the endothelium of lung donors in combination with recipient PBMC with or without PGD on the development of luminal occlusion. Methods Segments of arteries were implanted into the aorta of immunodeficient mice. Mice were divided into six treatment groups: group A mice with aortic vessels from PGD grade ≥ 2 (PGD+) patients were reconstituted with the respective allogeneic recipient PBMC, group B mice additionally received recipient CD4+CD25high Treg cells. Group C mice with aortic vessels from PGD grade ≤ 1 (PGD-) patients received recipient PBMC and group D mice additionally CD4+CD25high Treg cells. Control group E mice received arteries from PGD+, group F mice from PGD- patients, both without PBMC reconstitution. Luminal occlusion was quantified histologically and systemic immune responses by quantification of plasma cytokine and chemokines etc. Results Luminal occlusion of aortic vessels as sign of TA was significantly more severe in PGD+ group E compared to those from PGD- group F control mice in the absence of PBMC which was paralleled by higher IFN-γ (p Conclusion We conclude that a pre-existing Th1 response of the donor endothelial system contributes to PGD development, which is further enhanced by alloreactive T cells.