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Enhancement of the antigenspecific cytotoxic T lymphocyteinducing ability in the PMDC11 leukemic plasmacytoid dendritic cell line via lentiviral vectormediated transduction of the caTLR4 gene

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The aim of the present study was to enhance the efficiency of leukemia immunotherapy by increasing the antigenspecific cytotoxic T lymphocyteinducing ability of leukemia cells. The leukemic plasmacytoid dendritic cell line PMDC05 containing the HLAA02/24 antigen, which was previously established in our laboratory (Laboratory of Hematology and Oncology, Graduate School of Health Sciences, Niigata University, Niigata, Japan), was used in the present study. It exhibited higher expression levels of CD80 following transduction with lentiviruses encoding the CD80 gene. This CD80expressing PMDC05 was named PMDC11. In order to establish a more potent antigenpresenting cell for cellular immunotherapy of tumors or severe infections, PMDC11 cells were transduced with a constitutively active (ca) tolllike receptor 4 (TLR4) gene using the TetOn system (caTLR4PMDC11). CD8+ T cells from healthy donors with HLAA02 were cocultured with mutant WT1 peptidepulsed PMDC11, lipopolysaccharide (LPS)stimulated PMDC11 or caTLR4PMDC11 cells. Interleukin (IL)2 (50 IU/ml) and IL7 (10 ng/ml) were added on day three of culture. Priming with mutant WT1 peptidepulsed PMDC11, LPSstimulated PMDC11 or caTLR4PMDC11 cells was conducted once per week and two thirds of the IL2/IL7 containing medium was replenished every 34 days. Immediately prior to the priming with these various PMDC11 cells, the cultured cells were analyzed for the secretion of interferon (IFN)γ in addition to the percentage and number of CD8+/WT1 tetramer+ T cells using flow cytometry. caTLR4PMDC11 cells were observed to possess greater antigenpresenting abilities compared with those of PMDC11 or LPSstimulated PMDC11 cells in a mixed leukocyte culture. CD8 T cells positive for the WT1 tetramer were generated following 34 weeks of culture and CD8+/WT1 tetramer+ T cells were markedly increased in caTLR4PMDC11primed CD8+ T cell culture compared with PMDC11 or LPSstimulated PMDC11primed CD8+ T cell culture. These CD8+ T cells cocultured with caTLR4PMDC11 cells were demonstrated to secrete IFNγ and to be cytotoxic to WT1expressing target cells. These data suggested that the antigenspecific cytotoxic T lymphocyte (CTL)inducing ability of PMDC11 was potentiated via transduction of the caTLR4 gene. The present study also suggested that caTLR4PMDC11 cells may be applied as potent antigenpresenting cells for generating antigenspecific CTLs in adoptive cellular immunotherapy against tumors and severe viral infections.
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Document Type: Research Article

Affiliations: 1: Laboratory of Hematology and Oncology, Graduate School of Health Sciences, Niigata University, Nagaoka, Niigata 9518518, Japan 2: Division of Hematology, Nagaoka Red Cross Hospital, Nagaoka, Niigata 9518518, Japan 3: Laboratory of Cellular and Molecular Therapy, Department of Physiology and Immunology, Medical School of the Free University Brussels (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium 4: CURE Vector Core & JCCC Vector Shared Resource Facility, University of California, Los Angeles, CA 90095, USA 5: Division of Hematology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Niigata University, Niigata 9518510, Japan

Publication date: August 1, 2015

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  • Molecular Medicine Reports is a monthly, peer-reviewed journal available in print and online, that includes studies devoted to molecular medicine, underscoring aspects including pharmacology, pathology, genetics, neurosciences, infectious diseases, molecular cardiology and molecular surgery. In vitro and in vivo studies of experimental model systems pertaining to the mechanisms of a variety of diseases offer researchers the necessary tools and knowledge with which to aid the diagnosis and treatment of human diseases.
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