Orthotopic tracheal transplantation using human bronchus: an original xenotransplant model of obliterative airway disorder
Julien Guihaire
TSI-Laboratory, University Heart Center Hamburg, Hamburg, Germany
Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany
Search for more papers by this authorRyo Itagaki
TSI-Laboratory, University Heart Center Hamburg, Hamburg, Germany
Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany
Search for more papers by this authorMandy Stubbendorff
TSI-Laboratory, University Heart Center Hamburg, Hamburg, Germany
Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany
Search for more papers by this authorXiaoqin Hua
TSI-Laboratory, University Heart Center Hamburg, Hamburg, Germany
Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany
Search for more papers by this authorTobias Deuse
TSI-Laboratory, University Heart Center Hamburg, Hamburg, Germany
Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany
Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany
University of California San Francisco (UCSF) Department of Surgery, Division of Cardiothoracic Surgery, Transplant and Stem Cell Immunobiology (TSI), Lab San Francisco, CA, USA
Search for more papers by this authorSebastian Ullrich
Department of Anatomy and Experimental Morphology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
Search for more papers by this authorElie Fadel
Thoracic and Vascular Surgery and Heart-Lung Transplantation, Marie Lannelongue Hospital, University of Paris Sud, Le Plessis Robinson, France
Search for more papers by this authorPeter Dorfmüller
Department of Pathology, Marie Lannelongue Hospital, University of Paris Sud, Le Plessis Robinson, France
Search for more papers by this authorRobert C. Robbins
Department of Cardiothoracic Surgery, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
Search for more papers by this authorHermann Reichenspurner
Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany
Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany
Search for more papers by this authorUdo Schumacher
Department of Anatomy and Experimental Morphology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
Search for more papers by this authorCorresponding Author
Sonja Schrepfer
TSI-Laboratory, University Heart Center Hamburg, Hamburg, Germany
Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany
Department of Cardiothoracic Surgery, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
University of California San Francisco (UCSF) Department of Surgery, Division of Cardiothoracic Surgery, Transplant and Stem Cell Immunobiology (TSI), Lab San Francisco, CA, USA
Correspondence
Sonja Schrepfer, Transplant and Stem Cell Immunobiology Lab (TSI), University Heart Center Hamburg, Martinistraße 52, Campus Research, N27, room 068, 20246 Hamburg, Germany.
Tel.: +49-40-74105-9982;
fax: +49-40-74105-9663;
e-mail: [email protected]
Search for more papers by this authorJulien Guihaire
TSI-Laboratory, University Heart Center Hamburg, Hamburg, Germany
Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany
Search for more papers by this authorRyo Itagaki
TSI-Laboratory, University Heart Center Hamburg, Hamburg, Germany
Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany
Search for more papers by this authorMandy Stubbendorff
TSI-Laboratory, University Heart Center Hamburg, Hamburg, Germany
Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany
Search for more papers by this authorXiaoqin Hua
TSI-Laboratory, University Heart Center Hamburg, Hamburg, Germany
Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany
Search for more papers by this authorTobias Deuse
TSI-Laboratory, University Heart Center Hamburg, Hamburg, Germany
Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany
Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany
University of California San Francisco (UCSF) Department of Surgery, Division of Cardiothoracic Surgery, Transplant and Stem Cell Immunobiology (TSI), Lab San Francisco, CA, USA
Search for more papers by this authorSebastian Ullrich
Department of Anatomy and Experimental Morphology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
Search for more papers by this authorElie Fadel
Thoracic and Vascular Surgery and Heart-Lung Transplantation, Marie Lannelongue Hospital, University of Paris Sud, Le Plessis Robinson, France
Search for more papers by this authorPeter Dorfmüller
Department of Pathology, Marie Lannelongue Hospital, University of Paris Sud, Le Plessis Robinson, France
Search for more papers by this authorRobert C. Robbins
Department of Cardiothoracic Surgery, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
Search for more papers by this authorHermann Reichenspurner
Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany
Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany
Search for more papers by this authorUdo Schumacher
Department of Anatomy and Experimental Morphology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
Search for more papers by this authorCorresponding Author
Sonja Schrepfer
TSI-Laboratory, University Heart Center Hamburg, Hamburg, Germany
Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany
Department of Cardiothoracic Surgery, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
University of California San Francisco (UCSF) Department of Surgery, Division of Cardiothoracic Surgery, Transplant and Stem Cell Immunobiology (TSI), Lab San Francisco, CA, USA
Correspondence
Sonja Schrepfer, Transplant and Stem Cell Immunobiology Lab (TSI), University Heart Center Hamburg, Martinistraße 52, Campus Research, N27, room 068, 20246 Hamburg, Germany.
Tel.: +49-40-74105-9982;
fax: +49-40-74105-9663;
e-mail: [email protected]
Search for more papers by this authorSummary
Bronchiolitis obliterans syndrome (BOS) is a main cause of allograft dysfunction and mortality after lung transplantation (LTx). A better understanding of BOS pathogenesis is needed to overcome this treatment-refractory complication. Orthotopic tracheal transplantation using human bronchus was performed in Brown Norway (BN) and nude (RNU) rats. Allografts were recovered in both strains at Day 7 (BN7, n = 6; RNU7, n = 7) or Day 28 (BN28, n = 6; RNU28, n = 6). Immune response of the host against the bronchial graft was assessed. Human samples from BOS patients were used to compare with the histological features of the animal model. Obstruction of the allograft lumen associated with significant infiltration of CD3+ and CD68+ cells was observed in the BN group on Day 28. Immune response from type 1 T-helper cells against the tracheal xenograft was higher in BN animals compared to nude animals on Days 7 and 28 (P < 0.001 and P = 0.035). Xenoreactive antibodies were significantly higher at Day 7 (IgM) and Day 28 (IgG) in the BN group compared to RNU (respectively, 37.6 ± 6.5 vs. 5.8 ± 0.7 mean fluorescence, P = 0.039; and 22.4 ± 3.8 vs. 6.9 ± 1.6 mean fluorescence, P = 0.011). Immunocompetent animals showed a higher infiltration of S100A4+ cells inside the bronchial wall after 28 days, associated with cartilage damage ranging from invasion to complete destruction. In vitro expression of S100A4 by human fibroblasts was higher when stimulated by mononuclear cells (MNCs) from BN rats than from RNU (2.9 ± 0.1 vs. 2.4 ± 0.1 mean fluorescence intensity, P = 0.005). Similarly, S100A4 was highly expressed in response to human MNCs compared to stimulation by T-cell-depleted human MNCs (4.3 ± 0.2 vs. 2.7 ± 0.1 mean fluorescence intensity, P < 0.001). Obliterative bronchiolitis has been induced in a new xenotransplant model in which chronic airway obstruction was associated with immune activation against the xenograft. Cartilage infiltration by S100A4+ cells might be stimulated by T cells.
Supporting Information
| Filename | Description |
|---|---|
| tri12854-sup-0001-SupInfo.docWord document, 14.5 MB |
Appendix S1. Methods. Figure S1. Classification of epithelial coverage in the bronchial allograft. Figure S2. Origin of the cells in the fibroproliferative lesions observed after transplantation. Figure S3. FACS analysis of human mononuclear cells (MNCs) used for in vitro stimulation of human fibroblasts. |
| tri12854-sup-0002-VideoS1.avivideo/avi, 13.1 MB | Video Clip S1. This video demonstrates the transplantation of human bronchi into the tracheal position of rats as preclinical in vivo research model to study pathobiological and pathophysiological processes in the development of OAD. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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