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Blood, 15 April 2002, Vol. 99, No. 8, pp. 2869-2879
IMMUNOBIOLOGY
Increased dendritic cell number and function following continuous
in vivo infusion of granulocyte macrophage-colony-stimulating factor
and interleukin-4
Saroj K. Basak,
Airi Harui,
Marina Stolina,
Sherven Sharma,
Kohnosuke Mitani,
Steven M. Dubinett, and
Michael D. Roth
From the Division of Pulmonary and Critical Care,
Department of Medicine, the Department of Microbiology, Immunology and
Molecular Genetics, and the Jonsson Comprehensive Cancer Center, UCLA
School of Medicine, Los Angeles; and the West Los Angeles Veterans
Affairs Medical Center, CA.
Dendritic cells (DCs) are rare antigen-presenting cells that
play a central role in stimulating immune responses. The
combination of recombinant granulocyte
macrophage-colony-stimulating factor (rGM-CSF) and
recombinant interleukin-4 (rIL-4) provides an important stimulus for
generating DCs from murine bone marrow precursors in vitro. Using
miniature osmotic pumps, we now demonstrate that continuous infusion of
these cytokines for 7 days had a similar effect in vivo, increasing the
number and function of splenic DCs. Administration of rGM-CSF/rIL-4 (10 µg/d each) increased the concentration of CD11+ DCs by
2.7-fold and the absolute number of splenic DCs by an average of
5.7-fold. DC number also increased in peripheral blood and lymph
nodes. The resultant DCs exhibited a different phenotype and function
than those in control mice or mice treated with rGM-CSF alone.
rGM-CSF/IL-4 increased both the myeloid
(CD11c+/CD11b+) and the lymphoid
(CD11c+/CD8 +) subpopulations,
whereas rGM-CSF increased only myeloid DCs. DCs were highly
concentrated in the T-cell areas of white pulp after rGM-CSF/IL-4
administration, whereas they were diffusely distributed throughout
white pulp, marginal zones, and red pulp in mice treated with
rGM-CSF alone. rGM-CSF/rIL-4 also significantly increased the
expression of major histocompatibility complex (MHC) class I and MHC
class II on CD11c+ cells and increased their capacity
to take up antigens by macropinocytosis and receptor-mediated
endocytosis. Splenic DCs generated in response to rGM-CSF/rIL-4 were
functionally immature in terms of allostimulatory activity, but this
activity increased after short-term in vitro culture. Systemic
treatment with rGM-CSF/rIL-4 enhanced the response to an
adenoviral-based vaccine and led to antigen-specific retardation in the
growth of established tumor. We conclude that systemic therapy with the
combination of rGM-CSF/rIL-4 provides a new approach for generating DCs
in vivo.
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