Orthotopic tracheal transplantation using human bronchus: an original xenotransplant model of obliterative airway disorder.
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.
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.
Julien
J
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.
Ryo
R
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.
Mandy
M
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.
Xiaoqin
X
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.|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.
Tobias
T
Deuse
Department of Anatomy and Experimental Morphology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Sebastian
S
Ullrich
Thoracic and Vascular Surgery and Heart-Lung Transplantation, Marie Lannelongue Hospital, University of Paris Sud, Le Plessis Robinson, France.
Elie
E
Fadel
Department of Pathology, Marie Lannelongue Hospital, University of Paris Sud, Le Plessis Robinson, France.
Peter
P
Dorfmüller
Department of Cardiothoracic Surgery, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
Robert C
RC
Robbins
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.
Hermann
H
Reichenspurner
Department of Anatomy and Experimental Morphology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Udo
U
Schumacher
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.
Sonja
S
Schrepfer
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001980:Bronchi / Q000637:transplantation*; D001989:Bronchiolitis Obliterans / Q000209:etiology*; D017252:CD3 Complex / Q000378:metabolism; D004195:Disease Models, Animal; D058501:Enzyme-Linked Immunospot Assay; D006084:Graft Rejection / Q000473:pathology; D006085:Graft Survival; D006801:Humans; D007107:Immune System; D016031:Liver Transplantation; D011184:Postoperative Period; D011897:Random Allocation; D051381:Rats; D011914:Rats, Inbred BN; D000071999:S100 Calcium-Binding Protein A4 / Q000378:metabolism; D014132:Trachea / Q000637:transplantation*; D014183:Transplantation, Heterologous; D016896:Treatment Outcome; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D017252:CD3 Complex; D000071999:S100 Calcium-Binding Protein A4; C067980:CD68 antigen, human; D000097382:CD68 Molecule
S100A; T cells; chronic rejection; humanized model; lung transplantation