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DOI: 10.1055/s-0039-1678897
Transplant Arteriosclerosis in Humanized Mice Reflects the Presence of Early Donor-Specific Antibodies in Lung Transplant Recipients and Is Controlled by Autologous Regulatory T Cells
Publikationsverlauf
Publikationsdatum:
28. Januar 2019 (online)
Introduction: Antibody-mediated rejection (AMR) is one of the main causes of graft failure after solid organ transplantation. Here, we studied the correlation of early DSA in clinical lung transplant recipients with transplant arteriosclerosis in a humanized mouse model.
Methods: Segments of the pericardiophrenic artery were procured from surplus donor lung tissue and were implanted into the abdominal aorta of immune deficient mice. Experiments were assigned into two groups. Eleven patients (47.8%) developed early DSA after transplantation, whereas 12 patients (52.17%) showed no DSA. The experimental mice were divided into five treatment groups. Group A mice received no human leukocyte reconstitution and served as negative controls. Group B mice received 5 × 106 allogeneic human peripheral blood mononuclear cells (PBMC DSA+) from the respective lung recipients with DSA. Group C mice received PBMC from the respective patients with DSA and enriched with additional CD4+CD25high cells representing putative Treg. Group D mice received PBMC from patients without DSA (PBMC DSA-). Group E mice received PBMC DSA- enriched with additional CD4+CD25high cells. Human leukocyte engraftment was monitored by FACS and development of transplant arteriosclerosis was histologically assessed 28 days after PBMC reconstitution.
Results: Group A showed only mild thickening of the intima (17.19 ± 9.10%). In group B, reconstituted with PBMC DSA+, intimal thickening resulting in obliteration of the vessel lumen was significantly more severe than in group D, reconstituted with PBMC DSA-(37.80 ± 7.75% vs. 12.8 ± 6.81%, p = 0.002). By contrast, in group C, reconstituted with PBMC DSA+ enriched with CD4+CD25high cells, intimal thickening was significant less severe than in group B (0.37 ± 8.19 vs. 37.90 ± 6.150%, p = 0.013). In group E, enriching Treg similarly suppressed transplant arteriosclerosis elicited by PBMC DSA- (0.06 ± 5.99 vs. 11.3 ± 6.81%, p = 0.012).
Conclusion: We conclude that peripheral leukocytes from lung recipients with early DSA transfer more severe transplant arteriosclerosis into humanized mice. Importantly, transplant arteriosclerosis elicited by PBMC patients with or without early DSA is similarly significant reduced by CD4+CD25high cells, indicating a potentially important target for future interventions in lung transplantation.