Transplant arteriosclerosis in humanized mice reflects chronic lung allograft dysfunction and is controlled by regulatory T cells

OBJECTIVE: Chronic lung allograft dysfunction (CLAD) is a severe complication of lung transplantation limiting long-term survival. We studied correlations between CLAD after clinical lung transplantation and leukocyte-mediated development of transplant arteriosclerosis (TA) in a humanized mouse model. The pericardiophrenic artery was procured from surplus tissue of donor lungs (n = 22) transplanted in our clinical program and was implanted into the abdominal aorta of immune-deficient mice. METHODS: Allogeneic human peripheral blood mononuclear cells (PBMCs) had been procured 1 day after lung transplantation from the respective recipients with or without enriching for CD4(+)CD25(high) T cells were used. TA was assessed in mice 28 days later by histology. The respective clinical lung recipients were later divided into 2 groups. Eight patients (36.3%) had developed CLAD 23 +/- 5 months after lung transplantation, whereas the remaining 14 (63.6%) did not develop CLAD within 25 +/- 5 months. RESULTS: In the PBMC CLAD+ group of mouse experiments, TA was significantly more severe than in the PBMC CLAD- group (39.9% +/- 13% vs 14.9% +/- 4% intimal thickening; P = .0081). Then, intimal thickening was significantly inhibited in the PBMC+ regulatory T cells CLAD+ group compared with the PBMC CLAD+ group (0.4% +/- 4% vs 39.9% +/- 13%; P = .003). In the experiments using PBMCs from lung recipients without CLAD, enriching regulatory T cells also suppressed the development of TA (0.9% +/- 3% PBMC CLAD- vs 14.9% +/- 4% PBMC+ regulatory T cells CLAD-; P = .001). CONCLUSIONS: Lung transplant recipients who later develop CLAD have peripheral leukocytes already at the time of transplant that transfer proinflammatory properties leading to TA in a humanized mouse model. TA remains sensitive to inhibition by autologous regulatory T cells, suggesting a cell therapy-based approach for the prevention of CLAD after lung transplantation.

• Siemeni, T.
• Knofel, A. K.
• Ius, F.
• Sommer, W.
• Salman, J.
• Bothig, D.
• Falk, C. S.
• Tudorache, I.
• Haverich, A.
• Warnecke, G.