Department of Pathology, Center for Immune Regulation (CIR), Oslo University Hospital-Rikshospitalet and University of Oslo, Oslo, Norway.
Department of Cardiology, Unit of lung transplantation, Rigshospitalet, Copenhagen, Denmark.
Thorax. 2016 Nov;71(11):1006-1011. doi: 10.1136/thoraxjnl-2016-208292. Epub 2016 Jun 21.
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.
肺泡巨噬细胞（AMFs）是肺功能的关键调节者，并且可能参与肺移植后的移植物排斥反应。最近在实验动物中的研究表明，大多数 AMFs 是胚胎起源的自我维持细胞，但关于人 AMFs 的发生和寿命的知识却很少。
为了在肺移植超过 100 周的患者中追踪 AMFs 的起源和寿命，我们从 10 名性别不匹配的肺移植患者中获得了经支气管活检。对这些标本进行 X/Y 染色体的联合原位杂交和巨噬细胞标志物的免疫荧光染色。此外，还评估了用人脐带血衍生的 CD34+细胞重建的人源化小鼠中 AMFs 的发育情况。
在移植后 2 年内，供体来源的 AMFs 数量保持不变。一部分 AMFs 局部增殖，表明至少一部分人 AMFs 具有自我更新的能力。人源化小鼠的肺中含有大量表达与单核细胞起源相容的标志物的人 AMFs 群体。此外，在肺移植患者中，我们发现受体单核细胞在移植后早期定植肺泡，并表现出随后的表型变化，符合向增殖成熟 AMFs 的分化。这导致供体和受体 AMFs 之间在 2 年内保持稳定的混合嵌合体。
人 AMFs 在肺实质中维持数年的发现表明，肺巨噬细胞移植可能是由功能失调的 AMFs 引起的疾病的一种可行的治疗选择。此外，在肺移植环境中，供体 AMFs 的长期存在可能对慢性移植物排斥反应的发展很重要。
