title: The role of recipient derived interleukin-17A in a murine orthotopic lung transplant model of restrictive chronic lung allograft dysfunction.
abstract: The single most important cause of late mortality after lung transplantation is chronic lung allograft dysfunction (CLAD). However, the pathological development of CLAD was not as simple as previously presumed and subclassification phenotypes, bronchiolitis obliterans syndrome (BOS) and restrictive CLAD (rCLAD), have been introduced. We want to re-investigate how CLAD manifests in the murine orthotopic lung transplant model and investigate the role of interleukin 17A (IL-17A) within this model. Orthotopic LTx was performed in CB57BL/6, IL-17 WT and IL-17 KO mice. In a first experiment, CB57BL/6 mice receiving an isograft (CB57BL/6) or allograft (BALB/C) were compared. In a second experiment IL-17 WT and IL-17 KO mice (both CB57BL/6 background) received an allograft (BALB/C). Mice received daily immunosuppression with steroids and cyclosporine and were sacrificed 10weeks after transplantation for histopathological analysis by an experienced lung pathologist. After murine orthotopic lung transplantation, the allograft histopathologically presented features of human rCLAD (i.e. overt inflammation, pleural/parenchymal fibrosis and obliterative bronchiolitis). In the IL-17A KO group, less inflammation in the bronchovascular axis (p=0.03) was observed and a non-significant trend towards less bronchovascular fibrosis, pleural/septal inflammation and fibrosis, and parenchymal inflammation and fibrosis when compared to WT mice. The major mismatch orthotopic lung transplant model resembles features of human rCLAD. IL-17A mediated immunity is involved in the inflammatory component, but had little influence on the degree of fibrosis. Further mechanistic and therapeutic studies in this mouse model are needed to fully understand the mechanisms in rCLAD.
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland; Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Laboratory of Respiratory Disease and Laboratory for Experimental Thoracic Surgery, Department of Clinical and Experimental Medicine, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Vandermeulen
authors.affiliation: Laboratory of Respiratory Disease and Laboratory for Experimental Thoracic Surgery, Department of Clinical and Experimental Medicine, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: Heigl
authors.affiliation: Laboratory of Respiratory Disease and Laboratory for Experimental Thoracic Surgery, Department of Clinical and Experimental Medicine, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Somers
authors.affiliation: Laboratory of Respiratory Disease and Laboratory for Experimental Thoracic Surgery, Department of Clinical and Experimental Medicine, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Vaneylen
authors.affiliation: Laboratory of Respiratory Disease and Laboratory for Experimental Thoracic Surgery, Department of Clinical and Experimental Medicine, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: S E
authors.initials: SE
authors.lastname: Verleden
authors.affiliation: Laboratory of Respiratory Disease and Laboratory for Experimental Thoracic Surgery, Department of Clinical and Experimental Medicine, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Bellon
authors.affiliation: Laboratory of Respiratory Disease and Laboratory for Experimental Thoracic Surgery, Department of Clinical and Experimental Medicine, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: De Vleeschauwer
authors.affiliation: Department of Pathology, UZ Leuven, Leuven, Belgium.
authors.forename: E K
authors.initials: EK
authors.lastname: Verbeken
authors.affiliation: Laboratory of Respiratory Disease and Laboratory for Experimental Thoracic Surgery, Department of Clinical and Experimental Medicine, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: D E
authors.initials: DE
authors.lastname: Van Raemdonck
authors.affiliation: Laboratory of Respiratory Disease and Laboratory for Experimental Thoracic Surgery, Department of Clinical and Experimental Medicine, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Vos
authors.affiliation: Laboratory of Respiratory Disease and Laboratory for Experimental Thoracic Surgery, Department of Clinical and Experimental Medicine, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: G M
authors.initials: GM
authors.lastname: Verleden
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
authors.forename: W
authors.initials: W
authors.lastname: Jungraithmayr
authors.affiliation: Laboratory of Respiratory Disease and Laboratory for Experimental Thoracic Surgery, Department of Clinical and Experimental Medicine, KU Leuven - University of Leuven, Leuven, Belgium. Electronic address: bart.vanaudenaerde@med.kuleuven.be.
authors.forename: B M
authors.initials: BM
authors.lastname: Vanaudenaerde
mesh_terms: D000402:Airway Obstruction / Q000188:drug therapy / Q000276:immunology*; D000818:Animals; D001989:Bronchiolitis Obliterans / Q000188:drug therapy / Q000276:immunology*; D002908:Chronic Disease; D016572:Cyclosporine / Q000627:therapeutic use; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology*; D016040:Lung Transplantation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013256:Steroids / Q000627:therapeutic use; D066027:Transplant Recipients; D014184:Transplantation, Homologous
chemical_list: D020381:Interleukin-17; D013256:Steroids; D016572:Cyclosporine
keywords: Chronic rejection; Interleukin-17A; Lung transplantation; Murine orthotopic lung transplant model