title: Halofuginone treatment reduces interleukin-17A and ameliorates features of chronic lung allograft dysfunction in a mouse orthotopic lung transplant model.
abstract: BACKGROUND
  Increasing evidence suggests that interleukin (IL)-17A plays an important role in chronic lung allograft dysfunction (CLAD), characterized by airway and lung parenchymal fibrosis, after lung transplantation. Halofuginone is a plant derivative that has been shown to inhibit Th17 differentiation. The purpose of this study was to examine the effect of halofuginone on CLAD development using a minor alloantigen‒mismatched mouse orthotopic lung transplant model.
  
  
  METHODS
  C57BL/6 recipient mice received an orthotopic left lung transplant from C57BL/10 donors, mismatched for minor antigens. Lung transplant recipients received daily intraperitoneal injections of 2.5 μg halofuginone or vehicle alone. Lung grafts were assessed on Days 7, 14, and 28 post-transplant.
  
  
  RESULTS
  Compared with control mice, on Day 28 post-transplant, lung grafts of mice treated with halofuginone showed a significant reduction in the percentage of obliterated airways (6.8 ± 4.7% vs 52.5 ± 13.8%, p < 0.01), as well as significantly reduced parenchymal fibrosis (5.5 ± 2.3% vs 35.9 ± 10.9%, p < 0.05). Immunofluorescent staining for IL-17A demonstrated a decreased number and frequency of IL-17A‒positive cells in halofuginone-treated lung grafts on Day 28, as compared with controls. Halofuginone treatment also decreased IL-17A and IL-22 transcripts at Day 14, transforming growth factor-β1 and matrix metalloproteinase-2 transcripts at Days 14 and 28.
  
  
  CONCLUSIONS
  The beneficial effect of halofuginone on development of airway and lung parenchymal fibrosis in the mouse lung transplant model highlights the important role of IL-17A in CLAD and merits further pre-clinical and clinical studies.
authors.affiliation: Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Oishi
authors.affiliation: Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Tereza
authors.initials: T
authors.lastname: Martinu
authors.affiliation: Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada; Department of Thoracic Surgery, University of Tokyo, Tokyo, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Sato
authors.affiliation: Department of Thoracic Surgery, Aging and Cancer, Tohoku University, Sendai, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsuda
authors.affiliation: Department of Thoracic Surgery, Kobe City Medical Center West Hospital, Kobe, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Hirayama
authors.affiliation: Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Juvet
authors.affiliation: Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Zehong
authors.initials: Z
authors.lastname: Guan
authors.affiliation: Department of Thoracic Surgery, Kansai Medical University, Osaka, Japan.
authors.forename: Tomohito
authors.initials: T
authors.lastname: Saito
authors.affiliation: Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Cypel
authors.affiliation: Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: David M
authors.initials: DM
authors.lastname: Hwang
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Keller
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts.
authors.forename: Malcolm R
authors.initials: MR
authors.lastname: Whitman
authors.affiliation: Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada. Electronic address: shaf.keshavjee@uhn.ca.
authors.forename: Shaf
authors.initials: S
authors.lastname: Keshavjee
mesh_terms: D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D020381:Interleukin-17 / Q000378:metabolism*; D016040:Lung Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D052999:Quinazolinones / Q000494:pharmacology*; D058504:Th17 Cells / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D020381:Interleukin-17; D010880:Piperidines; D011500:Protein Synthesis Inhibitors; D052999:Quinazolinones; C010176:halofuginone
keywords: IL-17; chronic lung allograft dysfunction; halofuginone; obliterative bronchiolitis; restrictive allograft syndrome