Pulmonary transplantation of alpha-1 antitrypsin (AAT)-transgenic macrophages provides a source of functional human AAT in vivo

Inherited deficiency of the antiprotease alpha-1 antitrypsin (AAT) is associated with liver failure and early-onset emphysema. In mice, in vivo lentiviral transduction of alveolar macrophages (AMs) has been described to yield protective pulmonary AAT levels and ameliorate emphysema development. We here investigated the pulmonary transplantation of macrophages (PMT) transgenic for AAT as a potential therapy for AAT deficiency-associated lung pathology. Employing third-generation SIN-lentiviral vectors expressing the human AAT cDNA from the CAG or Cbx-EF1 alpha promoter, we obtained high-level AAT secretion in a murine AM cell line as well as murine bone marrow-derived macrophages differentiated in vitro (AAT M phi). Secreted AAT demonstrated a physiologic glycosylation pattern as well as elastase-inhibitory and anti-apoptotic properties. AAT M phi preserved normal morphology, surface phenotype, and functionality. Furthermore, in vitro generated murine AAT M phi successfully engrafted in AM-deficient Csf2rb(-/-) mice and converted into a CD11c(+)/Siglec-F+ AM phenotype as detected in bronchoalveolar lavage fluid and homogenized lung tissue 2 months after PMT. Moreover, human AAT was detected in the lung epithelial lining fluid of transplanted animals. Efficient AAT expression and secretion were also demonstrated for human AAT M phi, confirming the applicability of our vectors in human cells.

Automated summary

The study investigated the potential therapy of pulmonary transplantation of macrophages transgenic for AAT in treating AAT deficiency-associated lung pathology. The results demonstrated that in vitro generated AAT transgenic macrophages successfully engrafted in mice and showed efficient AAT expression and secretion, indicating the applicability of the vectors in human cells.