1.Rhamnogalacturonan II is a Toll-like receptor 4 agonist that inhibits tumor growth by activating dendritic cell-mediated CD8+ T cells.
Sung Nam PARK ; Kyung Tae NOH ; Young Il JEONG ; In Duk JUNG ; Hyun Kyu KANG ; Gil Sun CHA ; Su Jung LEE ; Jong Keun SEO ; Dae Hwan KANG ; Tae Ho HWANG ; Eun Kyung LEE ; Byungsuk KWON ; Yeong Min PARK
Experimental & Molecular Medicine 2013;45(2):e8-
We evaluated the effectiveness of rhamnogalacturonan II (RG-II)-stimulated bone marrow-derived dendritic cells (BMDCs) vaccination on the induction of antitumor immunity in a mouse lymphoma model using EG7-lymphoma cells expressing ovalbumin (OVA). BMDCs treated with RG-II had an activated phenotype. RG-II induced interleukin (IL)-12, IL-1beta, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) production during dendritic cell (DC) maturation. BMDCs stimulated with RG-II facilitate the proliferation of CD8+ T cells. Using BMDCs from the mice deficient in Toll-like receptors (TLRs), we revealed that RG-II activity is dependent on TLR4. RG-II showed a preventive effect of immunization with OVA-pulsed BMDCs against EG7 lymphoma. These results suggested that RG-II expedites the DC-based immune response through the TLR4 signaling pathway.
Acute-Phase Proteins/metabolism
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Adaptor Proteins, Vesicular Transport/metabolism
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Animals
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Antigens, CD14/metabolism
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Bone Marrow Cells/cytology/drug effects
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CD8-Positive T-Lymphocytes/*immunology
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Carrier Proteins/metabolism
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Cell Differentiation/drug effects
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Cell Nucleus/drug effects/metabolism
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Cell Proliferation/drug effects
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Cytokines/biosynthesis
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Dendritic Cells/cytology/drug effects/enzymology/*immunology
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Enzyme Activation/drug effects
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Lymphocyte Activation/*drug effects
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Membrane Glycoproteins/metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mitogen-Activated Protein Kinases/metabolism
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Myeloid Differentiation Factor 88/metabolism
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NF-kappa B/metabolism
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Neoplasms/immunology/*pathology
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Pectins/*pharmacology
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Phenotype
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Protein Transport/drug effects
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Receptors, Chemokine/metabolism
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Signal Transduction/drug effects
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T-Lymphocytes, Cytotoxic/cytology/drug effects
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Toll-Like Receptor 4/*agonists/metabolism
2.Suicidal cancer vaccine enhances anti-tumor immunotherapeutic effect and its safety in the treatment of ovarian cancer.
Yu KANG ; Cong-jian XU ; Xi-shi LIU ; Zhi-min SHAO ; Zhou-luo OU ; Jian-ming LUO ; Chao-qua WU ; Cui-ping ZHONG ; Jian-ren GU
Chinese Journal of Oncology 2006;28(9):654-657
OBJECTIVETo study the anti-tumor immunotherapeutic effect induced by the suicidalcancer vaccine FC/TK, and to evaluate the safety of this vaccine.
METHODSThe suicidal cancer vaccine, named FC/TK, was prepared by fusion of suicide gene (HSVI,-TK gene) -modified ovarian carcinoma NuTu-19 cells with rat bone marrow-derived dendritic cells (DCs). The morphology of FC/TK was evaluated by scanning electron microscopy. The stimulatory effect of FC/TK on T cells was determined by T cell proliferation assay. In immunotherapeutic studies in vivo, Fischer344 rats were injected subcutaneously with NuTu-19 cells, followed by treatment of FC/TK on days 7 and 14, compared to controls treated with irradiated FC/TK, FC or PBS, respectively. Tumor incidence and volume were measured in 90 days after challenge. To determine the killing effect of FC/TK in vivo, TUNEL assays were applied to detect apoptotic cell death in spleen of vaccinated rats with prodrug ganciclovir administration.
RESULTSFC/TK cells were of irregular shape with surface membrane processes. Compared to the control groups, FC/TK significantly promoted T cell proliferation (P <0.01). The rats vaccinated with FC/TK and FC significantly inhibited the tumor growth compared to rats vaccinated with irradiated FC/TK (P <0.05) or with PBS ( P <0.01). The immunotherapeutic effect induced by FC/TK was similar to that using FC. Fluorescence microscopy showed that fluorescein-stained FC/TK cells migrated into spleen also showed to be TUNEL-positive, suggesting that the FC/TK cells were killed by ganciclovir in vivo.
CONCLUSIONOur data indicate that suicidal cancer vaccine is an effective and safe therapy for ovarian carcinoma and may serve as a broadly applicable approach for other cancer vaccines in the future.
Animals ; Apoptosis ; drug effects ; Cancer Vaccines ; immunology ; Cell Fusion ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Dendritic Cells ; cytology ; immunology ; Female ; Ganciclovir ; pharmacology ; Genes, Transgenic, Suicide ; Herpesvirus 1, Human ; enzymology ; genetics ; Immunotherapy ; methods ; Microscopy, Electron, Scanning ; Microscopy, Fluorescence ; Neoplasms, Experimental ; enzymology ; pathology ; therapy ; Ovarian Neoplasms ; enzymology ; pathology ; therapy ; Rats ; Rats, Inbred F344 ; Survival Analysis ; T-Lymphocytes ; drug effects ; metabolism ; pathology ; Thymidine Kinase ; genetics ; metabolism ; Transfection