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Prepublished online as a Blood First Edition Paper on August 8, 2002; DOI 10.1182/blood-2002-04-1063.
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Blood, 1 December 2002, Vol. 100, No. 12, pp. 4169-4176
NEOPLASIA
Comparative analysis of murine marrow-derived dendritic cells
generated by Flt3L or GM-CSF/IL-4 and matured with immune stimulatory
agents on the in vivo induction of antileukemia responses
Brenda J. Weigel,
Narender Nath,
Patricia A. Taylor,
Angela Panoskaltsis-Mortari,
Wei Chen,
Arthur M. Krieg,
Kenneth Brasel, and
Bruce R. Blazar
From the University of Minnesota Cancer Center and
Department of Pediatrics, Division of Pediatric Hematology/Oncology and
Blood & Marrow Transplant, Minneapolis; the Department of Veteran
Affairs Medical Center and the Department of Internal Medicine,
University of Iowa College of Medicine, Iowa City; the Coley
Pharmaceutical Group, Wellesley, MA; and the Departments of
Immunobiology and Discovery Research, Immunex Corporation, Seattle, WA.
Bone marrow (BM)-derived dendritic cells (DCs) cultured in
granulocyte-macrophage colony-stimulating factor (GM-CSF) and
interleukin 4 (IL-4) have been used to generate antitumor immune
responses. The cytokine Flt3 ligand (Flt3L) also has been shown to
generate BM DCs. We sought to determine if DCs generated by using Flt3L then matured with lipopolysaccharide (LPS) could lead to DCs with in
vivo anti-acute myelogenous leukemia (anti-AML) activity. LPS and tumor necrosis factor  (TNF-) are effective agents for
maturing DCs; however, they have potential in vivo toxicities.
Cytosine-phosphorothioate-guanine oligodeoxynucleotides (CpGs) are
considered relatively nontoxic, potent activators of DC function and
maturation in vitro and in vivo. We investigated whether CpGs would be
comparable to TNF- or LPS for the maturation of
GM-CSF/IL-4-generated DCs. DCs cultured with GM-CSF/IL-4 and matured
with TNF-, LPS, or CpG produced a greater allogeneic T-cell response
compared with Flt3L/LPS-generated DCs. All 4 distinct DC types were
pulsed with AML-lysate and administered before tumor challenge produced
an increase in the total number of splenic anti-AML-specific cytotoxic
T-lymphocyte precursors and led to significantly (P  .0001) improved survival compared with nonvaccinated controls.
GM-CSF/IL-4/LPS was superior to Flt3L/LPS for generating anti-AML
effects in vivo. Whereas TNF- was comparable to LPS in conferring on
GM-CSF/IL-4 DCs anti-AML effects in vivo, CpGs were superior to LPS.
These data have important clinical implications and are the first to
show that Flt3L-generated DCs can provide antitumor protection and that
nontoxic agents such as CpGs and Flt3L may be useful in the clinical
development of DC vaccines.
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