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Blood, Vol. 93 No. 2 (January 15), 1999:
pp. 655-666
Selective Expansion of Alveolar Macrophages In Vivo
by Adenovirus-Mediated Transfer of the Murine Granulocyte-Macrophage
Colony-Stimulating Factor cDNA
Stefan Worgall,
Ravi Singh,
Philip L. Leopold,
Robert J. Kaner,
Neil R. Hackett,
Norbert Topf,
Malcolm A.S. Moore, and
Ronald G. Crystal
From the Division of Pulmonary and Critical Care Medicine, The New
York Hospital-Cornell Medical Center, New York, NY; and James Ewing
Laboratory of Developmental Hematopoiesis, Memorial Sloan-Kettering
Cancer Center, New York, NY.
Based on the hypothesis that genetic modification of freshly
isolated alveolar macrophages (AM) with the granulocyte-macrophage colony-stimulating factor (GM-CSF) cDNA would induce AM to proliferate, this study focuses on the ability of adenoviral (Ad) vectors to transfer and efficiently express the murine (m) GM-CSF cDNA in murine
AM with consequent expansion in the number of AM in vitro and in vivo.
To demonstrate that an Ad vector can effectively transfer and express
genes in AM, murine AM recovered by bronchoalveolar lavage from the
lung of Balb/c mice were infected with an Ad vector coding for green
fluorescent protein (GFP) in vitro and expressed GFP in a
dose-dependent fashion. Infection of AM with an Ad vector containing an
expression cassette coding for mGM-CSF led to GM-CSF expression and to
AM proliferation in vitro. When AM infected with AdGFP were returned to
the respiratory tract of syngeneic recipient mice, GFP-expressing cells
could still be recovered by bronchoalveolar lavage 2 weeks later. In
vitro infection of AM with AdmGM-CSF and subsequent transplantation of
the genetically modified AM to the lungs of syngeneic recipients led to
GM-CSF expression in vivo. Strikingly, the AM recovered by lavage 5 weeks after transplantation demonstrated an increased rate of
proliferation, and the total number of alveolar macrophages was
1.9-fold greater than controls. Importantly, the increase in the
numbers of AM was selective (ie, other inflammatory cell numbers were
unchanged), and there was no modification to the lung architecture.
Thus, it is feasible to genetically modify AM with Ad vectors and to use this strategy to modify the behavior of AM in vivo. Based on the
importance of AM in the primary defense of the respiratory epithelial
surface, this strategy may be useful in enhancing pulmonary defenses in
immunodeficiency states.
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