Augmented Proliferation of Human Alveolar Macrophages After Allogeneic Bone Marrow Transplantation

Abstract

After allogeneic bone marrow transplantation (allo-BMT), recipient alveolar macrophages (AM) are gradually replaced by AM of the donor origin. An influx of mononuclear phagocytes of donor origin to the lung is responsible for the repopulation, but the detailed kinetics remain unclear. We therefore studied 24 BMT recipients who underwent bronchoalveolar lavage (BAL) from 24 to 83 days after BMT. AM cell number, size, morphology, proliferating ability, and genotype of AM were measured. Before day 50, the number and size of AM in BAL fluid were similar to those of normal nonsmokers. However, after day 50, the mean number of AM increased threefold and the mean cell size decreased due to the increase of small AM. These small cells are presumably of donor origin based on DNA fingerprinting analysis and based on fluorescence in situ hybridization for the Y chromosome in a sex-mismatched case. Immunohistochemistry and cell cycle analysis demonstrated that the increase in AM number coincided with a remarkable increase of AM expressing proliferating cell nuclear antigen, suggesting that small AM are proliferating. This is the first report representing that augmented proliferation of donor AM in situ may contribute to the reconstitution of AM population after BMT.

Macrophages in experimental rat lung isografts and allografts: infiltration and proliferation in situ

“…Some authors claim that AMs have almost totally lost their proliferative potential [31], whereas other publications demonstrate that the renewal of AMs may only be accounted for by local proliferation [17,32,33]. Our data are in line with the assumption that local proliferation contributes considerably to the homeostasis of AMs in healthy and inflamed lungs [19,20,22]. However, the proliferation rates published so far for normal and pathological lungs are clearly below the amount of proliferation found in our experimental model.…”

“…application might result in low local doses of 3 H-thymidine in the lung and therefore, limit the detection of proliferating AMs [20]. Cell nuclei in the S-phase of the cell cycle are labeled in the living animal, whereas in other studies, BAL cells were collected and analyzed in an in vitro culture system [21,22,31]. In our experimental model, S-phase AMs are identified by double-staining with mAb ED1 and anti-BrdU, allowing the unequivocal identification of AMs.…”

“…During inflammation, 3 H-thymidine incorporation was seen in up to 6% of the AMs [19 -21]. Nakata et al [22], who analyzed proliferating cells by detection of the proliferating cell nuclear antigen after allogeneic bone marrow transplantation in humans, also obtained comparable results. Taken together, these studies indicate that recruitment of blood monocytes to the alveolar space and proliferation of AMs in situ are not mutually exclusive and probably occur concomitantly in an intact organism.…”

Lack of effect of bone marrow transplantation on airway hyperresponsiveness in an asthmatic

“…More importantly, DNA fingerprint analysis reveals that, on day 83, the donor bands predominate but the recipient genotype is still seen. 7 This suggests that the minority of alveolar macrophages may be of recipient origin on day 98 in this asthmatic. Another important population for antigen presentation in the lung is the dendritic cell.…”

“…Recently, however, the kinetics of alveolar macrophages have been demonstrated after allogeneic BMT. 7 The proliferation of alveolar macrophages in situ may contribute to reconstitution of the alveolar macrophage population 50 days after BMT. More importantly, DNA fingerprint analysis reveals that, on day 83, the donor bands predominate but the recipient genotype is still seen.…”