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J Thorac Cardiovasc Surg. 2019 Feb 28. pii: S0022-5223(19)30519-7. doi: 10.1016/j.jtcvs.2019.01.134. [Epub ahead of print]

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

Author information

1
Division of Cardiac, Thoracic, Transplantation, and Vascular Surgery, Hannover Medical School, Hannover, Germany.
2
Division of Cardiac, Thoracic, Transplantation, and Vascular Surgery, Hannover Medical School, Hannover, Germany; German Centre for Lung Research BREATH site, Hannover Medical School, Hannover, Germany.
3
IFB-Tx, Hannover Medical School, Hannover, Germany.
4
Division of Cardiac, Thoracic, Transplantation, and Vascular Surgery, Hannover Medical School, Hannover, Germany; German Centre for Lung Research BREATH site, Hannover Medical School, Hannover, Germany. Electronic address: warnecke.gregor@mh-hannover.de.

Abstract

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+CD25high 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.

KEYWORDS:

lung transplant; regulatory T cells; rejection

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