Transplant Arteriosclerosis in Humanized Mice Reflects Chronic Lung Allograft Dysfunction: An 8-Year Follow-Up Analysis

Background: Chronic lung allograft dysfunction (CLAD) is the leading cause of mortality in lung transplant recipients after the first year post-transplantation. We investigated the correlation between CLAD and leukocyte-mediated transplant arteriosclerosis (TA) development using a humanized mouse model.

Methods: The pericardiophrenic artery was obtained from surplus donor lung tissue (n = 31) transplanted in our clinical program between 2012 and 2020. These arteries were implanted into the abdominal aorta of immune-deficient mice. Outcomes were compared between patients who developed CLAD (PBMC CLAD+ group) and those who did not (PBMC CLAD− group), with a follow-up period of 71 ± 26 months. Allogeneic human peripheral blood mononuclear cells (PBMCs) were collected from the respective recipients 1 day after lung transplantation. TA in mice was assessed 28 days post-implantation using histology.

Results: During the study period, 31 lung transplant recipients were included. Of these, 11 patients (35.4%) developed CLAD at 67 ± 30 months post-transplant, while the remaining 20 patients in the PBMC CLAD− group (64.5%) did not develop CLAD within 43 ± 30 months. In the mouse experiments, the PBMC CLAD+ group exhibited significantly more severe TA than the PBMC CLAD− group (41.9% ± 12% versus 15.9% ± 4% intimal thickening, p = 0.0089). Mortality within 8 years was 41.94% (13 patients).

Conclusion: Lung transplant recipients who later develop CLAD possess peripheral leukocytes at the time of transplantation with proinflammatory characteristics. When transferred into a humanized mouse model, these leukocytes contribute to the development of transplant arteriosclerosis.

Publication History

Article published online:
11 February 2025