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Blood, 15 February 2002, Vol. 99, No. 4, pp. 1246-1252
IMMUNOBIOLOGY
Reduced tissue macrophage population in the lung by anticancer
agent cyclophosphamide: restoration by local granulocyte
macrophage-colony-stimulating factor gene transfer
Michael Santosuosso,
Maziar Divangahi,
Anna Zganiacz, and
Zhou Xing
From the Department of Pathology and Molecular Medicine
and the Division of Infectious Diseases, Centre for Gene Therapeutics,
McMaster University, Hamilton, Ontario, Canada.
Granulocytopenia is thought to be the sole mechanism underlying the
increased susceptibility to bacterial infection in hosts with
anticancer chemotherapy. Little is known about the functional state of
tissue macrophage populations in such hosts. Using a model of
chemotherapy-induced leukopenia, the number and function of alveolar
macrophages (AMS) were examined during and after multiple injections of
an anticancer agent, cyclophosphamide (CP). Although CP quickly reduced
peripheral blood leukocytes, the number of these cells rebounded
quickly 3 to 4 days after the withdrawal of CP. Accompanying blood
leukopenia was a profound reduction in the number of AMs.
Contrary to the rapid onset of blood leukopenia, tissue macrophage
deficiency was a more chronic process that worsened gradually as the CP
regimen continued. Of importance, in contrast to blood leukopenia,
which restored itself shortly after CP withdrawal, tissue
macrophage deficiency was not immediately self-recoverable in spite
of a restored number of circulating leukocytes. Although AMS had a
decreased ability to proliferate during, but not after, the CP regimen,
these cells retained a normal ability to release tumor necrosis
factor- and nitric oxide. To identify the potential therapeutics for
recovering macrophages, a gene vector expressing granulocyte
macrophage-colony-stimulating factor (GM-CSF) was delivered either
systemically or locally. GM-CSF transgene was able to expand macrophage
populations only when delivered to the lung after, but not during, the
CP regimen. This study thus identifies tissue macrophage deficiency as
a mechanism of weakened innate immunity by chemotherapy and suggests
the usefulness of topical GM-CSF transgene expression for restoring
innate immunity in the lung.
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