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Prepublished online as a Blood First Edition Paper on November 7, 2002; DOI 10.1182/blood-2002-02-0378.
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Blood, 15 March 2003, Vol. 101, No. 6, pp. 2184-2190
GENE THERAPY
Retrovirus-mediated IL-7 expression in leukemic dendritic cells
generated from primary acute myelogenous leukemias enhances their
functional properties
Concha Bello-Fernández,
Jana Stasakova,
Alexander Renner,
Nicole Carballido-Perrig,
Margit Koening,
Martina Waclavicek,
Otto Madjic,
Leopold Oehler,
Oskar Haas,
José M. Carballido,
Michael Buschle, and
Walter Knapp
From the Institute of Immunology, Vienna International
Research Cooperation Center (VIRCC), University of Vienna,
Vienna, Austria; Novartis Forschunsginstitut, Vienna,
Austria; CCRI St Anna Children's Hospital, Vienna, Austria;
Division of Hematology, Internal Medicine I University of Vienna,
Austria; and Intercell AG, Vienna,
Austria.
Myeloid lineage-derived dendritic cells (DCs) are considered the
professional antigen-presenting cell type responsible for eliciting
T-cell-mediated immune responses. Acute myelogenous leukemia (AML) is
a disease in which tumor antigens are expressed by the malignant clone
that also has the potential to differentiate into DC-like cells
(leukemic DCs) with antigen-presenting capacity. This study
investigated whether the constitutive expression of the cytokine
interleukin-7 (IL-7) in primary AML cells during their differentiation
toward leukemic DCs results in superior antigen-presenting
cells. A bicistronic retroviral vector encoding the IL-7
cytokine and the surface immunoselectable low-affinity nerve
growth factor receptor (LNGFr) gene was constructed and used for
transduction experiments. A serum-free system was used to transduce and
differentiate leukemic cells toward leukemic DCs. The study included 8 patients with AML. The transduction efficiency with the
cytokine vector varied among patients, ranging from 5% to 30% as
judged by LNGFr expression. The leukemic origin of the transduced cells
was confirmed in a patient with a chromosomal translocation t(9:11) by
fluorescence in situ hybridization analysis. Cytokine
modified-cells consistently secreted IL-7 (mean, 415 pg
± 190/106 cells/48 hours; n = 5). We demonstrate that
IL-7-transduced cells are included in the differentiated
leukemic DC subset, and, as shown in a particular case, that about half
of the mature CD80+ and CD83+ populations
coexpress the LNGFr transgene. In addition, IL-7-modified leukemic cells induce stronger allo-T-cell stimulation and higher amounts of IL-2 production in T cells compared with control groups. Finally, cytokine-transduced leukemic DCs can effectively prime and
generate cytotoxic T lymphocytes against autologous leukemic blasts.
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Leukemia-Derived Immature Dendritic Cells Differentiate into Functionally Competent Mature Dendritic Cells That Efficiently Stimulate T Cell Responses
J. Immunol.,
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[Abstract]
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