Efficient generation of highly immunocompetent dendritic cells from peripheral blood of patients with hepatitis C virus-related hepatocellular carcinoma

Background & aims Immunotherapy using dendritic cells (DCs) is a promising cancer therapy. The success of this therapy depends on the function of induced DCs. However, there has been no consensus on optimal conditions for DC preparation in vitro for immunotherapy of hepatocellular carcinoma (HCC) patients. To address relevant issues, we evaluated the procedures to induce DCs that efficiently function in hepatitis C virus (HCV)-related HCC. Methods We studied immunological data from 14 HCC patients. The DC preparation and the surface markers were assessed by flow cytometric analysis. Four different additional activation stimuli (Method I, medium alone; Method II, with OK-432; Method III, with IL-1β + IL-6 + TNF-α; Method IV, with IL-1β + IL-6 + TNF-α + PGE2) were tested and the functions of DCs were confirmed by examination of the ability of phagocytosis, cytokine production and allogeneic mixed lymphocyte reaction (MLR). Results The numbers of DCs induced and their cytokine production ability were not different between healthy controls and HCC patients. T-cell stimulatory activity of DCs in MLR was significantly lower in HCC patients than in healthy controls. The maturation of DCs with OK-432 boosted production of cytokines and chemokines, such as IL-2, IL-12p70, IFN-γ, TNF-α, IL-13 and MIP1α, and restored T-cell stimulatory activity of DCs in MLR. Conclusions The clinically approved compound OK-432 is a candidate for highly immunocompetent DC preparation and may be considered as a key drug for immunotherapy of HCV-related HCC patients. © 2014 Published by Elsevier B.V

Prolonged recurrence-free survival following OK432-stimulated dendritic cell transfer into hepatocellular carcinoma during transarterial embolization

金沢大学医薬保健研究域医学系Despite curative locoregional treatments for hepatocellular carcinoma (HCC), tumour recurrence rates remain high. The current study was designed to assess the safety and bioactivity of infusion of dendritic cells (DCs) stimulated with OK432, a streptococcus-derived anti-cancer immunotherapeutic agent, into tumour tissues following transcatheter hepatic arterial embolization (TAE) treatment in patients with HCC. DCs were derived from peripheral blood monocytes of patients with hepatitis C virus-related cirrhosis and HCC in the presence of interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor and stimulated with 0.1 KE/ml OK432 for 2 days. Thirteen patients were administered with 5 × 106 of DCs through arterial catheter during the procedures of TAE treatment on day 7. The immunomodulatory effects and clinical responses were evaluated in comparison with a group of 22 historical controls treated with TAE but without DC transfer. OK432 stimulation of immature DCs promoted their maturation towards cells with activated phenotypes, high expression of a homing receptor, fairly well-preserved phagocytic capacity, greatly enhanced cytokine production and effective tumoricidal activity. Administration of OK432-stimulated DCs to patients was found to be feasible and safe. Kaplan-Meier analysis revealed prolonged recurrence-free survival of patients treated in this manner compared with the historical controls (P = 0.046, log-rank test). The bioactivity of the transferred DCs was reflected in higher serum concentrations of the cytokines IL-9, IL-15 and tumour necrosis factor-α and the chemokines CCL4 and CCL11. Collectively, this study suggests that a DC-based, active immunotherapeutic strategy in combination with locoregional treatments exerts beneficial anti-tumour effects against liver cancer. © 2010 The Authors. Clinical and Experimental Immunology © 2010 British Society for Immunology

2017～2019年度 関西大学研究拠点形成支援経費研究成果報告書

目次・研究成果の概要・2-1　工藤 宏人・宮前 翼・上田 正人・村山 憲弘・林 順一 "ノーリア骨格をテンプレートとした空孔内に水酸基を有する架橋化合物の合成とそれらの金属イオン包接性能" ネットワークポリマー論文集 vol.41, No.2, 65 - 71 (2020).・2-2　Mitsuaki Matsuoka, Kaho Yokoyama, Kohei Okura, Norihiro Murayama, Masato Ueda, Makio Naito " Synthesis of Geopolymers from Mechanically Activated Coal Fly Ash and Improvement of Their Mechanical Properties" Minerals 9, 791- 801 (2019).・2-3　Daisuke Shimoyama, Ryo Sekiya, Hiroto Kudo, Takeharu Haino, "Feet-to-Feet Connected Trisresorcinarenes" Organic Letters 22, 352 - 356 (2019).・2-4　Masato Ueda, Masahiko Ikeda, Shigeo Mori, Kenji Doi, Hisashi Kitagaki, Shuntaro Terauchi "Mechanical Properties of Additively Manufactured Porous Titanium with Sub-Millimetre Structural Units" Materials Transactions Vol.60, No.9, 1792 - 1798 (2019).・2-5　五十井 浩平・白杉 文香・松岡 光昭・林 順一・村山 憲弘 "種々のMg-Fe系複合酸化物を用いた希薄水溶液中のホウ素およびヒ素の除去" 環境資源工学 66, 29 - 35 (2019).・2-6　Toru Maruyama, Mitsuyoshi Tamaki, Keisuke Nakamura, Gou Nakamura "EFFECT OF MOLTEN METAL TEMPERATURE ON MOLD FILLING IN EVAPORATIVE PATTERN CASTING" International Journal of Metalcasting 13, 611–617 (2019).・2-7　Ryuta Saito, Toru Maruyama, Toshiki Nakamura, Hitoshi Yanagitani, Takahiro Sakai, Kouji Nakamoto "Influence of Tellurium Addition to Spheroidal Graphite Cast Iron on the Number of Graphite Particles" International Journal of Metalcasting Vol.13, 3, 571-577 (2018).・2-8　Masato Ueda, Rika Yamaguchi, Chika Fujita, Masahiko Ikeda "Control of Cell Adhesion on Titanium Dioxide by Light Irradiation" Materials Science Forum Vol.941, 2507 - 2512 (2018).・2-9　Hiroto Kudo, Mari Fukunaga, Kohei Shiotsuki, Hiroya Takeda, Hiroki Yamamoto, Takahiro Kozawa, Takeo Watanabe "Synthesis of hyperbranched polyacetals containing C-(4-t-butylbenz)calix[4]resorcinarene: Resist properties for extreme ultraviolet (EUV) lithography" Reactive and Functional Polymers 131, 361 - 367 (2018).・2-10　大隈 修・前 一廣・林 順一 "直接液化による豪州ビクトリア褐炭の高度利用 : 改新BCLプロセスによる化学原料の生産" Journal of the Japan Institute of Energy 98, 17 - 26 (2019).・2-11　Issei Suzuki, Ayako Kakinuma, Masato Ueda, Takahisa Omata "Flux growth of β-NaGaO₂ single crystals" Journal of Crystal Growth 504, 26 -30 (2018).・2-12　上田 正人、坂本 貴則、池田 勝彦 "電気抵抗率の精密測定による純チタンの組織評価" 環境資源工学 65, 74 -76 (2018).・2-13　Satoshi Imasaka, Hiroyasu Ishii, Jun\u27ichi Hayashi, Sadao Araki, Hideki Yamamoto "Synthesis of CHA-type titanosilicate zeolites using titanium oxide as Ti source and evaluation of their physicochemical properties" Microporous and Mesoporous Materials 273, 243-248 (2019).・2-14　Hiroto Kudo, Shizuya Ohori, Hiroya Takeda, Hiroki Ogawa, Takeo Watanbe, Hiroki Yamamoto, Takahiro Kozawa "Synthesis and Property of Tannic Acid Derivatives and Their Application for Extreme Ultraviolet Laser Lithography System" Journal of Photopolymer Science and Technology Vol.31, 221 - 225 (2018).・2-15　Hiroto Kudo, Tsubasa Miyamae, Kouta Kitagawa, Kohei Isoi, Norihiro Murayama, Jun\u27ichi Hayashi " Synthesis and Metal-Complexation Ability of Cross-Linking Materials Containing Noria-Templated Cavities with Pendant Carboxylic Acid Groups" Chemistry Select 3, 2223 - 2228 (2018).・2-16　上田 正人、池田 勝彦、土井 研児、 森 重雄、北垣 壽、寺内 俊太郎、関 あずさ "骨部分置換用ポーラスチタン : ポリグリコール酸 : 炭酸カルシウム複合体の開発" 高分子論文集 Vol.75, No.1, 69 - 74 (2018).・2-17　Alexandru C Sonoc, Jacob Jeswiet, Norihiro Murayama, Junji Shibata "A study of the application of Donnan dialysis to the recycling of lithium ion batteries" Hydrometallurgy 175, 133 - 143 (2018).2-3は、著作権の関係により非公開としております。2-8は、著作権の関係により非公開としております。2-9は、著作権の関係により非公開としております。2-10は、著作権の関係により非公開としております。2-11は、著作権の関係により非公開としております。2-16は、著作権の関係により非公開としております

Astroglial Connexin43 as a Potential Target for a Mood Stabiliser

Mood disorders remain a major public health concern worldwide. Monoaminergic hypotheses of pathophysiology of bipolar and major depressive disorders have led to the development of monoamine transporter-inhibiting antidepressants for the treatment of major depression and have contributed to the expanded indications of atypical antipsychotics for the treatment of bipolar disorders. In spite of psychopharmacological progress, current pharmacotherapy according to the monoaminergic hypothesis alone is insufficient to improve or prevent mood disorders. Recent approval of esketamine for treatment of treatment-resistant depression has attracted attention in psychopharmacology as a glutamatergic hypothesis of the pathophysiology of mood disorders. On the other hand, in the last decade, accumulated findings regarding the pathomechanisms of mood disorders emphasised that functional abnormalities of tripartite synaptic transmission play important roles in the pathophysiology of mood disorders. At first glance, the enhancement of astroglial connexin seems to contribute to antidepressant and mood-stabilising effects, but in reality, antidepressive and mood-stabilising actions are mediated by more complicated interactions associated with the astroglial gap junction and hemichannel. Indeed, several depressive mood-inducing stress stimulations suppress connexin43 expression and astroglial gap junction function, but enhance astroglial hemichannel activity. On the other hand, monoamine transporter-inhibiting antidepressants suppress astroglial hemichannel activity and enhance astroglial gap junction function, whereas several non-antidepressant mood stabilisers activate astroglial hemichannel activity. Based on preclinical findings, in this review, we summarise the effects of antidepressants, mood-stabilising antipsychotics, and anticonvulsants on astroglial connexin, and then, to establish a novel strategy for treatment of mood disorders, we reveal the current progress in psychopharmacology, changing the question from “what has been revealed?” to “what should be clarified?”

Tumor cell apoptosis induces tumor-specific immunity in a CC chemokine receptor 1- and 5-dependent manner in mice

金沢大学がん研究所がん病態制御The first step in the generation of tumor immunity is the migration of dendritic cells (DCs) to the apoptotic tumor, which is presumed to be mediated by various chemokines. To clarify the roles of chemokines, we induced apoptosis using suicide gene therapy and investigated the immune responses following tumor apoptosis. We injected mice with a murine hepatoma cell line, BNL 1ME A.7R.1 (BNL), transfected with HSV-thymidine kinase (tk) gene and then treated the animals with ganciclovir (GCV). GCV treatment induced massive tumor cell apoptosis accompanied with intratumoral DC infiltration. Tumor-infiltrating DCs expressed chemokine receptors CCR1 and CCR5, and T cells and macrophages expressed CCL3, a ligand for CCR1 and CCR5. Moreover, tumor apoptosis increased the numbers of DCs migrating into the draining lymph nodes and eventually generated a specific cytotoxic cell population against BNL cells. Although GCV completely eradicated HSV-tk-transfected BNL cells in CCR1-, CCR5-, or CCL3-deficient mice, intratumoral and intranodal DC infiltration and the subsequent cytotoxicity generation were attenuated in these mice. When parental cells were injected again after complete eradication of primary tumors by GCV treatment, the wild-type mice completely rejected the rechallenged cells, but the deficient mice exhibited impairment in rejection. Thus, we provide definitive evidence indicating that CCR1 and CCR5 and their ligand CCL3 play a crucial role in the regulation of intratumoral DC accumulation and the subsequent establishment of tumor immunity following induction of tumor apoptosis by suicide genes. © Society for Leukocyte Biology.全文公開20091