Pulmonary macrophage transplantation therapy

Abstract

SUMMARYBone marrow transplantation is an effective cell therapy but requires myeloablation, which increases infection-risk and mortality. Recent lineage-tracing studies documenting that resident macrophage populations self-maintain independent of hematologic progenitors prompted us to consider organ-targeted, cell-specific therapy. Here, using GM-CSF receptor-β deficient (Csf2rb−/−) mice that develop a myeloid cell disorder identical to hereditary pulmonary alveolar proteinosis (hPAP) in children with CSF2RA/CSF2RB mutations, we show that pulmonary macrophage transplantation (PMT) of either wild-type or Csf2rb-gene-corrected macrophages without myeloablation was safe, well-tolerated, and that one administration corrected the lung disease, secondary systemic manifestations, normalized disease-related biomarkers, and prevented disease-specific mortality. PMT-derived alveolar macrophages persisted for at least one year as did therapeutic effects. Results identify mechanisms regulating alveolar macrophage population size in health and disease, indicate that GM-CSF is required for phenotypic determination of alveolar macrophages, and support translation of PMT as the first specific therapy for children with hPAP.

NFAT5-Regulated Macrophage Polarization Supports the Proinflammatory Function of Macrophages and T Lymphocytes

“…By contrast, in the adoptive transfer experiments we inoculated a large number of a homogeneous type of macrophage, likely tilting the equilibrium toward an immune response dominated by the transferred BMDM and not by endogenous myeloid cells. This dominant role of adoptively transferred macrophages has been reported in other systems such as the correction of lung alveolar proteinosis by adoptive transfer of GM-CSF receptorcompetent macrophages in Csf2rb-deficient mice (54). Apart from these points, when interpreting the role of NFAT5 in how macrophages influence tumors, we should also consider that persistent inflammation upon tissue damage can drive tumor promotion (55-57) through cytokines like IL-6 and TNF-a (58,59).…”

Alveolar macrophage development in mice requires L-plastin for cellular localization in alveoli

“…8 Alveolar epithelial cells produce GM-CSF, 12 and localization to the alveolar microenvironment is required for precursors to differentiate into alveolar macrophages. 13 Under homeostatic conditions, alveolar macrophages self-renew throughout the lifespan to maintain a full complement, without repopulating from circulating blood monocytes. Despite the importance of establishing a normal complement of alveolar macrophages, key factors that regulate the timing and localization of alveolar macrophage precursors during neonatal development are incompletely described.…”

Traitement de la protéinose alvéolaire par transplantation intrapulmonaire de macrophages

“…La nature de la cellule à modifier peut être limitante, mais dans les cas de protéinoses alvéolaires secondaires à une mutation du récep-teur du GM-CSF, cette approche pouvait s'avérer efficace. Une équipe américaine a récemment élégamment confirmé cette hypothèse chez la souris [21]. …”