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Original article
Long-term persistence of human donor alveolar macrophages in lung transplant recipients
  1. Ibon Eguíluz-Gracia1,
  2. Hans Henrik Lawaetz Schultz2,
  3. Liv I B Sikkeland3,
  4. Elena Danilova1,
  5. Are M Holm3,
  6. Cornelis J H Pronk4,
  7. William W Agace4,
  8. Martin Iversen2,
  9. Claus Andersen5,
  10. Frode L Jahnsen1,
  11. Espen S Baekkevold1
  1. 1Department of Pathology, Center for Immune Regulation (CIR), Oslo University Hospital-Rikshospitalet and University of Oslo, Oslo, Norway
  2. 2Department of Cardiology, Unit of lung transplantation, Rigshospitalet, Copenhagen, Denmark
  3. 3Department of Respiratory Medicine, Institute for Clinical Medicine, Oslo University Hospital-Rikshospitalet and University of Oslo, Oslo, Norway
  4. 4Immunology Section, Lund University, Lund, Sweden
  5. 5Department of Pathology, Rigshospitalet, Copenhagen University, Copenhagen, Denmark University, Copenhagen, Denmark
  1. Correspondence to Dr Espen S Baekkevold, Department of Pathology, Center for Immune Regulation (CIR), Oslo University Hospital-Rikshospitalet and University of Oslo, Oslo N-0027, Norway; espen.s.bakkevold{at}rr-research.no

Abstract

Background 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.

Methods 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.

Results 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.

Conclusions 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.

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Footnotes

  • Contributors IE-G performed all the analysis of human specimens; FLJ and ESB designed the study and wrote the manuscript; ED, CJHP and WWA generated the humanised mice; LIBS, AMH, HHLS, MI and CA selected and recruited the patients included in the study.

  • Funding This work was partly supported by the Research Council of Norway through its Centers of Excellence funding scheme, project number 179573 and grants from the South Eastern Norway Regional Health Authority, project number 1012105.

  • Competing interests None declared.

  • Ethics approval Norwegian Regional Committee for Medical Research Ethics, The National Committee on Health Research Ethics in Denmark and the Lund/Malmö Animal Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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