Abstract Rationale Autoimmune pulmonary alveolar proteinosis (aPAP) results from impaired alveolar macrophage function due to neutralizing anti-GM-CSF autoantibodies. Whole-lung lavage (WLL) removes abnormally accumulated surfactant; however, the mechanism underlying its long-lasting clinical benefit remains unclear. We hypothesized that, beyond surfactant removal, WLL modulates immune responses that contribute to sustained improvement. To elucidate this, we analyzed peripheral blood mononuclear cells (PBMCs) obtained longitudinally during the course of the WLL procedure. Methods We retrospectively analyzed nine patients with aPAP who underwent WLL at our institution between 2018 and 2024. PBMCs were collected at baseline, one day, and seven days after WLL. Monocyte subsets—nonclassical, intermediate, and classical monocytes (CMs)—as well as lymphocytes were analyzed by flow cytometry. Changes in immune-cell phenotypes were analyzed and correlated with clinical outcomes. Results Among nine patients with aPAP, eight underwent bilateral and one unilateral WLL, yielding a total of 17 WLL procedures for PBMC analysis; samples were available pre-WLL (n = 17), on day 1 (n = 15), and on day 7 (n = 16). One day after WLL, circulating monocytes increased significantly from baseline. Their phenotypic analysis revealed a significant expansion of HLA-DRlow immature CMs (n = 15 WLL, P = 0.0004) with diminished antigen-presenting, co-stimulatory, and activation capacities, characterized by reduced expression of CD86, CD69, and PD-L1. By day 7, these changes had returned to baseline. This transient increase in circulating HLA-DRlow CMs after WLL, suggesting the mobilization of immature HLA-DRlow CMs from the bone marrow into the peripheral blood and their subsequent recruitment to the lung. The significant increase in HLA-DRlow CMs at day 1 was observed in patients with radiographic improvement (P = 0.0078), whereas no such increase was seen in those with persistent or progressive opacities, all of whom subsequently required additional interventions, suggesting that HLA-DRlow CMs may serve as a potential biomarker for favorable clinical outcomes in patients with aPAP. Conclusion Our findings indicate that WLL not only eliminates excess alveolar surfactant but also transiently modulates systemic immunity by mobilizing immature monocytes from the bone marrow into the circulation. This transient immunologic change was associated with radiographic improvement, suggesting that the reconstitution of peripheral monocyte subsets by WLL may contribute to the sustained clinical benefits observed in patients with aPAP. This abstract is funded by: Grant-in-Aid for Scientific Research (KAKENHI), Japan Society for the Promotion of Science Grant Numbers: 22K08256 and 22K08284; and the Shinnihon Foundation of Advanced Medical Treatment Research.
Tajima et al. (Fri,) studied this question.
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