title: Long-term persistence of human donor alveolar macrophages in lung transplant recipients.
abstract: Alveolar macrophages (AMFs) are critical regulators of lung function, and may participate in graft rejection following lung transplantation. Recent studies in experimental animals suggest that most AMFs are self-maintaining cells of embryonic origin, but knowledge about the ontogeny and life span of human AMFs is scarce.
  
  
  
  To follow the origin and longevity of AMFs in patients with lung transplantation for more than 100 weeks, we obtained transbronchial biopsies from 10 gender-mismatched patients with lung transplantation. These were subjected to combined in situ hybridisation for X/Y chromosomes and immunofluorescence staining for macrophage markers. Moreover, development of AMFs in humanised mice reconstituted with CD34+ umbilical cord-derived cells was assessed.
  
  
  
  The number of donor-derived AMFs was unchanged during the 2 year post-transplantation period. A fraction of the AMFs proliferated locally, demonstrating that at least a subset of human AMFs have the capacity to self-renew. Lungs of humanised mice were found to abundantly contain populations of human AMFs expressing markers compatible with a monocyte origin. Moreover, in patients with lung transplantation we found that recipient monocytes seeded the alveoli early after transplantation, and showed subsequent phenotypical changes consistent with differentiation into proliferating mature AMFs. This resulted in a stable mixed chimerism between donor and recipient AMFs throughout the 2-year period.
  
  
  
  The finding that human AMFs are maintained in the lung parenchyma for several years indicates that pulmonary macrophage transplantation can be a feasible therapeutic option for patients with diseases caused by dysfunctional AMFs. Moreover, in a lung transplantation setting, long-term persistence of donor AMFs may be important for the development of chronic graft rejection.
authors.affiliation: Department of Pathology, Center for Immune Regulation (CIR), Oslo University Hospital-Rikshospitalet and University of Oslo, Oslo, Norway.
authors.forename: Ibon
authors.initials: I
authors.lastname: Eguíluz-Gracia
authors.affiliation: Department of Cardiology, Unit of lung transplantation, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Hans Henrik Lawaetz
authors.initials: HH
authors.lastname: Schultz
authors.affiliation: Department of Respiratory Medicine, Institute for Clinical Medicine, Oslo University Hospital-Rikshospitalet and University of Oslo, Oslo, Norway.
authors.forename: Liv I B
authors.initials: LI
authors.lastname: Sikkeland
authors.affiliation: Department of Pathology, Center for Immune Regulation (CIR), Oslo University Hospital-Rikshospitalet and University of Oslo, Oslo, Norway.
authors.forename: Elena
authors.initials: E
authors.lastname: Danilova
authors.affiliation: Department of Respiratory Medicine, Institute for Clinical Medicine, Oslo University Hospital-Rikshospitalet and University of Oslo, Oslo, Norway.
authors.forename: Are M
authors.initials: AM
authors.lastname: Holm
authors.affiliation: Immunology Section, Lund University, Lund, Sweden.
authors.forename: Cornelis J H
authors.initials: CJ
authors.lastname: Pronk
authors.affiliation: Immunology Section, Lund University, Lund, Sweden.
authors.forename: William W
authors.initials: WW
authors.lastname: Agace
authors.affiliation: Department of Cardiology, Unit of lung transplantation, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Iversen
authors.affiliation: Department of Pathology, Rigshospitalet, Copenhagen University, Copenhagen, Denmark University, Copenhagen, Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: Andersen
authors.affiliation: Department of Pathology, Center for Immune Regulation (CIR), Oslo University Hospital-Rikshospitalet and University of Oslo, Oslo, Norway.
authors.forename: Frode L
authors.initials: FL
authors.lastname: Jahnsen
authors.affiliation: Department of Pathology, Center for Immune Regulation (CIR), Oslo University Hospital-Rikshospitalet and University of Oslo, Oslo, Norway.
authors.forename: Espen S
authors.initials: ES
authors.lastname: Baekkevold
mesh_terms: D000328:Adult; D000818:Animals; D001706:Biopsy; D005260:Female; D005455:Fluorescent Antibody Technique; D006084:Graft Rejection / Q000473:pathology; D006801:Humans; D017403:In Situ Hybridization; D016040:Lung Transplantation; D016676:Macrophages, Alveolar / Q000473:pathology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D066027:Transplant Recipients
keywords: Lung Transplantation; Macrophage Biology; Pulmonary alveolar proteinosis