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

Autor: Janosz E; Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.; REBIRTH - Research Center for Translational Regenerative Medicine, Hannover, Germany., Hetzel M; Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.; REBIRTH - Research Center for Translational Regenerative Medicine, Hannover, Germany., Spielmann H; Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.; REBIRTH - Research Center for Translational Regenerative Medicine, Hannover, Germany., Tumpara S; Department of Internal Medicine, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany., Rossdam C; Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany., Schwabbauer M; Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.; REBIRTH - Research Center for Translational Regenerative Medicine, Hannover, Germany., Kloos D; Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.; REBIRTH - Research Center for Translational Regenerative Medicine, Hannover, Germany., von Kaisenberg C; Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany., Schambach A; Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.; REBIRTH - Research Center for Translational Regenerative Medicine, Hannover, Germany., Buettner FFR; Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany., Janciauskiene S; Department of Internal Medicine, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany., Lachmann N; Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.; REBIRTH - Research Center for Translational Regenerative Medicine, Hannover, Germany., Moritz T; Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany. moritz.thomas@mh-hannover.de.; REBIRTH - Research Center for Translational Regenerative Medicine, Hannover, Germany. moritz.thomas@mh-hannover.de.
Jazyk: angličtina
Zdroj: Gene therapy [Gene Ther] 2021 Sep; Vol. 28 (9), pp. 477-493. Date of Electronic Publication: 2021 Jul 19.
DOI: 10.1038/s41434-021-00269-3
Abstrakt: 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-EF1α 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 MΦ). Secreted AAT demonstrated a physiologic glycosylation pattern as well as elastase-inhibitory and anti-apoptotic properties. AAT MΦ preserved normal morphology, surface phenotype, and functionality. Furthermore, in vitro generated murine AAT MΦ 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 MΦ, confirming the applicability of our vectors in human cells.
(© 2021. The Author(s).)
Databáze: MEDLINE
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