2021/12/04 更新

写真a

トウマ マキ
藤間 真紀
TOUMA Maki
所属
教育研究院 自然科学系 地球・生物科学系列 准教授
自然科学研究科 生命・食料科学専攻 准教授
理学部 理学科 准教授
職名
准教授
外部リンク

学位

  • 理学博士 ( 2000年3月   新潟大学 )

経歴(researchmap)

  • 新潟大学   理学部 理学科   助教

    2017年4月 - 現在

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  • 新潟大学   自然科学研究科   助教

    2013年3月 - 現在

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  • 新潟大学   理学部 生物学科   助教

    2013年3月 - 2017年3月

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  • 新潟大学   自然科学研究科   助教

    2009年1月 - 2013年2月

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経歴

  • 新潟大学   教育研究院 自然科学系 地球・生物科学系列   准教授

    2021年9月 - 現在

  • 新潟大学   自然科学研究科 生命・食料科学専攻   准教授

    2021年9月 - 現在

  • 新潟大学   理学部 理学科   准教授

    2021年9月 - 現在

  • 新潟大学   理学部 理学科   助教

    2017年4月 - 2021年8月

  • 新潟大学   自然科学研究科 生命・食料科学専攻   助教

    2013年3月 - 2021年8月

  • 新潟大学   自然科学研究科 生命・食料科学専攻   助教

    2013年3月 - 2021年8月

  • 新潟大学   生体制御学   助教

    2013年3月 - 2017年3月

  • 新潟大学   自然科学研究科   助教

    2009年1月 - 2013年2月

▶ 全件表示

 

論文

  • MicroRNA-342 inhibits tumor growth via targeting chemokine CXCL12 involved in macrophages recruitment/activation. 査読 国際誌

    Yijun Tian, Sayaka Matsui, Maki Touma, Qiong Wu, Kenkichi Sugimoto

    Genes to cells : devoted to molecular & cellular mechanisms   23 ( 12 )   1009 - 1022   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    MicroRNAs (miRNAs) play important roles in initiation, development, progression and metastasis of tumors. MiR-342 has been reported as a tumor suppressor or an onco-miRNA based on functions or expression changes in various types of cancers. However, the biological roles and underlying molecular mechanisms of miR-342 in tumorigenesis remain largely unknown. Here, we found that miR-342 was expressed significantly less in a murine MS-K tumor cell line that showed riched blood vessels. Over-expression of miR-342 in MS-K cells inhibited cell proliferation, colony formation, reduced frequency of S phase population in vitro and suppressed tumor growth in vivo. Moreover, increasing miR-342 impeded blood vessels formation and accumulation of macrophages (CD11b+ ) in tumors. By bioinformatic analysis and dual-luciferase reporter assays, chemokine CXCL12 was identified as a direct target of miR-342. Restored Cxcl12 expression in MS-K-miR-342 cells could rescue cell proliferation in vitro. In MS-K-miR-342 tumor-infiltrated macrophages, expression of proangiogenic genes (Vegf-A and Thbs1) and M2-subtype macrophage markers (Cd163, Dectin1 and Ym1) was significantly down-regulated compared with controls. Moreover, lower level of Cxcl12 and its receptor Cxcr4 was observed in the macrophages of MS-K-miR-342 tumors, and MS-K-miR-342 derived miR-342, but not endogenous miR-342, might contribute to Cxcl12 suppression in TAM. These results suggest that miR-342 is involved in MS-K tumor growth as a tumor suppressor by targeting chemokine CXCL12.

    DOI: 10.1111/gtc.12650

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  • CCL11-induced eosinophils inhibit the formation of blood vessels and cause tumor necrosis 査読

    Yanjiang Xing, Yijun Tian, Takamasa Kurosawa, Sayaka Matsui, Maki Touma, Takanori Yanai, Qiong Wu, Kenkichi Sugimoto

    GENES TO CELLS   21 ( 6 )   624 - 638   2016年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    We previously demonstrated that IL-18 and CCL11 were highly expressed in an NFSA tumor cell line that showed limited angiogenesis and severe necrosis. However, IL-18 was not responsible for the immune cell accumulation and necrosis. Here, we attempted to clarify the relevance of CCL11 in angiogenesis and tumor formation. We established CCL11-overexpressing MS-K cell clones (MS-K-CCL11) to assess the role of CCL11 in immune cell accumulation and angiogenesis. The MS-K-CCL11 cells did not form tumors in mice. MS-K-CCL11-conditioned medium (CM) and recombinant CCL11 induced macrophage and eosinophil differentiation from bone marrow cells. The MS-K-CCL11-CM effectively recruited the differentiated eosinophils. Furthermore, the eosinophils damaged the MS-K, NFSA and endothelial cells in a dose-dependent manner. Administration of an antagonist of CCR3, a CCL11 receptor, to NFSA tumor-bearing mice restored the blood vessel formation and blocked the eosinophil infiltration into the NFSA tumors. Furthermore, other CCL11-overexpressing LM8 clones were established, and their tumor formation ability was reduced compared to the parental LM8 cells, accompanied by increased eosinophil infiltration, blockade of angiogenesis and necrosis. These results indicate that CCL11 was responsible for the limited angiogenesis and necrosis by inducing and attracting eosinophils in the tumors.

    DOI: 10.1111/gtc.12371

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  • The atypical IκB protein IκB(NS) is important for Toll-like receptor-induced interleukin-10 production in B cells. 査読

    Miura M, Hasegawa N, Noguchi M, Sugimoto K, Touma M

    Immunology   147 ( 4 )   453 - 463   2016年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/imm.12578

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  • Inhibition of blood vessel formation in tumors by IL-18-polarized M1 macrophages 査読

    Yanjiang Xing, Yijun Tian, Takamasa Kurosawa, Sayaka Matsui, Maki Touma, Qiong Wu, Kenkichi Sugimoto

    GENES TO CELLS   21 ( 3 )   287 - 295   2016年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    We previously showed that interleukin (IL)-18 produced by NFSA cells induced the M1 type of macrophages in NFSA tumors, caused the destruction of endothelial cells invitro and may have resulted in the necrosis of NFSA tumors by enhancing macrophage phagocytosis and cytotoxicity. However, the effect of IL-18 on blood vessel formation invivo has not been elucidated. MS-K cells do not express il-18, and they form tumors with well-developed blood vessels. Here, we established IL-18-over-expressing MS-K cell clones (MS-K-IL-18) to address the roles of IL-18 in angiogenesis. The over-expression of IL-18 inhibited the proliferation rate of the MS-K-IL-18 cells invitro and blood vessel formation in the MS-K-IL-18 tumors. Interestingly, CD14-positive cells from the MS-K-IL-18 tumor had up-regulated expression of the M1-type macrophage marker il-6 and down-regulated expression of interferon (ifn)-. Furthermore, FACS analysis showed more accumulation of CD11b+/CD80+ M1 macrophages in the MS-K-IL-18 tumors than in the parental MS-K tumor. Moreover, an invitro coculture assay showed that MS-K-IL-18-conditioned medium (CM) stimulated macrophages to induce the apoptosis of endothelial cells. Cumulatively, our data showed that IL-18 inhibited tumor blood vessel formation invivo.

    DOI: 10.1111/gtc.12329

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  • Induction of autoimmune gastritis by neonatal thymectomy requires autoantibodies and is prevented by anti-FcγR antibodies. 査読

    Saito T, Suenaga S, Fujii M, Kushida Y, Kawauchi Y, Suzuki K, Touma M, Hosono M

    Cellular immunology   300   1 - 8   2016年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.cellimm.2015.10.004

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  • Bcl11b prevents the intrathymic development of innate CD8 T cells in a cell intrinsic manner 査読

    Satoshi Hirose, Maki Touma, Rieka Go, Yoshinori Katsuragi, Yoshiyuki Sakuraba, Yoichi Gondo, Manabu Abe, Kenji Sakimura, Yukio Mishima, Ryo Kominami

    INTERNATIONAL IMMUNOLOGY   27 ( 4 )   205 - 215   2015年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    If Bcl11b activity is compromised, CD4(+)CD8(+) double-positive ( DP) thymocytes produce a greatly increased fraction of innate CD8(+) single-positive ( SP) cells highly producing IFN-gamma, which are also increased in mice deficient of genes such as Itk, Id3 and NF-kappa B1 that affect TCR signaling. Of interest, the increase in the former two is due to the bystander effect of IL-4 that is secreted by promyelocytic leukemia zinc finger-expressing NKT and gamma delta T cells whereas the increase in the latter is cell intrinsic. Bcl11b zinc-finger proteins play key roles in T cell development and T cell-mediated immune response likely through TCR signaling. We examined thymocytes at and after the DP stage in Bcl11b(F/S826G) CD4cre, Bcl11b(F/+) CD4cre and Bcl11b(+/S826G) mice, carrying the allele that substituted serine for glycine at the position of 826. Here we show that Bcl11b impairment leads to an increase in the population of TCR alpha beta(high)CD44(high)CD122(high) innate CD8SP thymocytes, together with two different developmental abnormalities: impaired positive and negative selection accompanying a reduction in the number of CD8SP cells, and developmental arrest of NKT cells at multiple steps. The innate CD8SP thymocytes express Eomes and secrete IFN-gamma after stimulation with PMA and ionomycin, and in this case their increase is not due to a bystander effect of IL-4 but cell intrinsic. Those results indicate that Bcl11b regulates development of different thymocyte subsets at multiple stages and prevents an excess of innate CD8SP thymocytes.

    DOI: 10.1093/intimm/dxu104

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  • Population doublings of murine CD4(+) memory T cells during continuous antigen stimulation in vivo 査読

    Yoshihiro Kushida, Jun-ya Ishida, Masato Fujii, Maki Touma, Masamichi Hosono

    CELLULAR IMMUNOLOGY   292 ( 1-2 )   45 - 52   2014年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    We investigated the expansion rate of CD4(+) memory T cells using a newly developed in vivo system. Neonatal thymectomy abrogates the subsequent production of T cells and induces autoimmune gastritis (AIG) by the activation of CD4(+) T cells; this disease was transferred into athymic nude mice through the inoculation of splenic CD4(+) memory T cells. The transferred CD4(+) T cells increased logarithmically in number during the first 2 months in the spleen of the recipients. The serial transfer of these splenocytes at two-month intervals revealed that the numbers of the AIG-transferable generations were inversely correlated with the age of the first AIG donors. The duration of the AIG-promoting capacity of CD4(+) T cells under continuous antigenic stimulation in vivo was approximately equivalent-one and a half years. These results indicate that there exists an intrinsic population doubling limit in memory CD4(+) T cells similar to that of self-renewing naive ones. (C) 2014 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.cellimm.2014.09.001

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  • Enhancement of phagocytosis and cytotoxicity in macrophages by tumor-derived IL-18 stimulation 査読

    Xu Henan, Naoka Toyota, Xing Yanjiang, Yuuki Fujita, Huang Zhijun, Maki Touma, Wu Qiong, Kenkichi Sugimoto

    BMB REPORTS   47 ( 5 )   286 - 291   2014年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:KOREAN SOCIETY BIOCHEMISTRY & MOLECULAR BIOLOGY  

    Inoculation of mice with the murine NFSA cell line caused the formation of large tumors with necrotic tumor cores. FACS analysis revealed accumulations of CD11b(+) cells in the tumors. Microarray analysis indicated that the NFSA cells expressed a high level of the pro-inflammatory factor interleukin-18 (il-18), which is known to play a critical role in macrophages. However, little is known about the physiological function of IL-18-stimulated macrophages. Here, we provide direct evidence that IL-18 enhances the phagocytosis of RAW264 cells and peritoneal macrophages, accompanied by the increased expression of tumor necrosis factor (tnf-a), interleukin-6 (il-6) and inducible nitric oxide synthase (Nos2). IL-18-stimulated RAW264 cells showed an enhanced cytotoxicity to endothelial F-2 cells via direct cell-to-cell interaction and the secretion of soluble mediators. Taken together, our results demonstrate that tumor-derived IL-18 plays an important role in the phagocytosis of macrophages and that IL-18-stimulated macrophages may damage tumor endothelial cells.

    DOI: 10.5483/BMBRep.2014.47.5.152

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  • A Dominant Trait Linked to Chromosome 1 in DBA/2 Mice for the Resistance to Autoimmune Gastritis Appears in Bone Marrow Cells 査読

    Masato Fujii, Kenji Suzuki, Satoru Suenaga, Mariko Wakatsuki, Yoshihiro Kushida, Maki Touma, Masamichi Hosono

    EXPERIMENTAL ANIMALS   63 ( 2 )   155 - 167   2014年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:INT PRESS EDITING CENTRE INC  

    Neonatal thynnectomy (NTx) induces autoimmune gastritis (AIG) in BALB/c mice, a model for human type A chronic atrophic gastritis, but not in DBA/2 mice and rarely in CDF1 mice (a hybrid of BALB/c and DBA/2 mice). The aim of this study was to clarify the mechanisms of AIG-resistance in mice bearing the dominant trait of DBA/2. Linkage groups associated with, and cells related to AIG resistance were examined with CDF1-BALB/c backcrosses. Intracellular staining and flow-cytometric bead array for several cytokines were performed on NTx BALB/c mice and NTx DBA/2-chimeric BALB/c mice receiving DBA/2-bone marrow cells. In NTx BALB/c mice, IFN-gamma-secreting CD4(+) T cells were increased, but not in NTx DBA/2 mice. Because V beta 6(+) T cell-bearing mice of half of their backcrosses developed AIG, but the other half of V beta 6(+) T cell-negative mice developed scarcely, resistance for AIG generation is associated with the presence of the MIs-1a locus on chromosome 1 in DBA/2 mice, which deletes V beta 6(+) T cells. NTx DBA/2-chimera BALB/c mice showed dominant production of IL-10 and resistance for AIG, although the deletion of V beta 6(+) T cells was found not to be a cause of AIG-resistance from MIs-1a locus segregation experiments. Although NTx DBA/2-chimeric BALB/c mice did not suffer from AIG, they brought immediate precursors of T cells for AIG. It is concluded that DBA/2 mice generate bone marrow-derived cells that produce anti-inflammatory cytokines to prevent the activation of AIG-T cells.

    DOI: 10.1538/expanim.63.155

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  • Role of FGF10 on tumorigenesis by MS-K 査読

    Kenkichi Sugimoto, Suzuka Yoshida, Yuka Mashio, Naoka Toyota, Yanjiang Xing, Henan Xu, Yuki Fujita, Zhijun Huang, Maki Touma, Qiong Wu

    GENES TO CELLS   19 ( 2 )   112 - 125   2014年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Murine MS-K and NFSA cell lines formed tumor after inoculation into mouse and both cell lines expressed high level of vascular endothelial growth factor-A (vegf-A) and produced same level of VEGF-A. However, poor blood vessel formation, and necrosis was significantly observed in NFSA-tumor, contrary to well-developed blood vessel formation in MS-K tumor. The microarray analysis showed high expression of fibroblast growth factor-10 (fgf-10) in MS-K than NFSA. In this report, the role of fgf-10 on tumor growth was studied. MS-K enhanced more proliferation of endothelial cells by direct co-culture than NFSA, and rFGF10 supported the proliferation of HUVEC in combination with VEGF-A. fgf-10-knocked down MS-K, MS-K (fgf-10-KD), proliferated slower in vitro and the tumorigenicity of them was also slower than control. The blood vessel formation in these MS-K (fgf-10-KD) clones was reduced compared with the MS-K (normal). qPCR analysis showed the suppression of vegf-A, vegf-C and fgfr-1-expression in the MS-K (fgf-10-KD) clones. Taken together, these results indicated that FGF10, which was produced from tumor cells, was essential for the proliferation of tumor cell itself and also supports proliferation of endothelial cells. Thus, FGF10 plays an important role for tumor growth by both paracrine and autocrine manner.

    DOI: 10.1111/gtc.12118

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  • Limited immune diversity in urodela: chronic transplantation responses occur even with family-disparate xenografts. 査読

    Kenjiroh Kinefuchi, Yoshihiro Kushida, Maki Touma, Masamichi Hosono

    Zoological science   30 ( 7 )   577 - 84   2013年7月

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    記述言語:英語  

    Urodele amphibians are thought to have poorer immune responses than evolutionary more ancestral vertebrate classes, such as bony fish. We investigated skin graft rejection and transplantation immunity in Urodele amphibians, Japanese newts, and Asiatic salamanders, and compared these findings to those from transplants in several species of frogs. The skin grafts used in this study were either allogeneic or xenogeneic. The mean survival time of the first set of allografts at 20°C was approximately 60 days for chronic responses in Urodela and 20 days for acute responses in Anura. As the graft survival times of urodeles were significantly longer than those of anurans, even when urodeles were repeatedly grafted from identical donors, there appear to be substantial differences in transplantation immunity between Urodela and Anura. These slow responses in Urodela may not be accompanied by the expansion of cytotoxic T cells, as observed in fish and anuran species, which are known to have functional major histocompatibility complex (MHC)-class I systems. In our study, approximately five histo-incompatible immunogenic components were found to be involved in chronic responses in newts. Similar chronic responses were also observed in xenograft rejection in newts. In contrast, xenografts were rejected in frogs due to an accelerated acute response, possibly involving natural killer cells. Our findings that some anti-allogeneic components appear to be shared with xenogeneic components indicate that the diversification of the acquired immune system is poorly developed in Urodela.

    DOI: 10.2108/zsj.30.577

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  • T cells affect thymic involution during puberty by inducing regression of the adrenal reticularis 査読

    Yoshihiro Kushida, Sayaka Kumagai, Ken Gotoh, Masato Fujii, Maki Touma, Masamichi Hosono

    JOURNAL OF PHYSIOLOGICAL SCIENCES   62 ( 3 )   173 - 184   2012年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER TOKYO  

    The thymus involutes after puberty, although the mechanism by which this process occurs remains poorly understood. The profile of thymic involution, which is inversely correlated with an increase in peripheral T cells, may indicate that the accumulation of T cells in the periphery is related to thymic atrophy. In this study, it was shown that the prevention of T cell generation delayed the initiation of thymic involution. The activation of T cells increased the serum concentration of glucocorticoid (GC) and thymic involution, which was completely prevented by adrenalectomy. In the adrenals of growing mice, the activity of the zona fasciculata, which produces GC, increased and plateaued by the weaning period; however, the zona reticularis (ZR), which produces dehydroepiandrosterone (DHEA) that has anti-GC actions, started to decline just before puberty. Thymic atrophy was preceded by the infiltration of activated T cells into the ZR and by the loss of ZR cells. Thus, T cells are involved in thymic involution, a process which was retarded by DHEA administration, through an increase in GC activity due to ZR cell-killing.

    DOI: 10.1007/s12576-012-0194-y

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  • Impaired B Cell Development and Function in the Absence of I kappa BNS 査読

    Maki Touma, Derin B. Keskin, Fumiko Shiroki, Ibuki Saito, Shigeo Koyasu, Ellis L. Reinherz, Linda K. Clayton

    JOURNAL OF IMMUNOLOGY   187 ( 8 )   3942 - 3952   2011年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC IMMUNOLOGISTS  

    I kappa BNS has been identified as a member of the I kappa B family of NF-kappa B inhibitors, which undergoes induction upon TCR signaling. Mice carrying a targeted gene disruption of I kappa BNS demonstrate dysregulation of cytokines in T cells, macrophages, and dendritic cells. I kappa BNS mediates both positive and negative gene regulation, depending on individual cell type and/or cytokine. In this study, we demonstrate an additional role for I kappa BNS in the B cell lineage. B cells from I kappa BNS knockout ( KO) mice were impaired in proliferative responses to LPS and anti-CD40. IgM and IgG3 Igs were drastically reduced in the serum of I kappa BNS KO mice, although I kappa BNS KO B cells exhibited a higher level of surface IgM than that found in wild-type mice. Switching to IgG3 was significantly reduced in I kappa BNS KO B cells. The in vitro induction of plasma cell development demonstrated that progression to Ab-secreting cells was impaired in I kappa BNS KO B cells. In agreement with this finding, the number of Ab-secreting cells in the spleens of I kappa BNS KO mice was reduced and production of Ag-specific Igs was lower in I kappa BNS KO mice after influenza infection as compared with wild-type mice. Additionally, I kappa BNS KO mice lacked B1 B cells and exhibited a reduction in marginal zone B cells. Thus, I kappa BNS significantly impacts the development and functions of B cells and plasma cells. The Journal of Immunology, 2011, 187: 3942-3952.

    DOI: 10.4049/jimmunol.1002109

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  • Effect of vegf gene knockdown on growth of the murine sarcoma cell line MS-K 査読

    Xiu Y. Zhong, Asami Yoshioka, Yuka Mashio, Toru Ikeda, Huijie Jiang, Maki Touma, Qiong Wu, ChangLiu Wang, Kenkichi Sugimoto

    GENES TO CELLS   16 ( 6 )   625 - 638   2011年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    The murine sarcoma cell line MS-K was previously established as a Ki-ras-positive cell line. Inoculation of this cell line under the flank of C3H/HeN mice results in the growth of large tumors with well-developed blood vessels within day 30 of transplantation without any metastasis because MS-K cells produce vascular endothelial growth factor (VEGF). To elucidate the role of VEGF in tumor formation in vivo, stable vegf-knockdown-MS-K clones were obtained using plasmid-based knockdown vectors. Interestingly, tumorigenesis was completely suppressed in a vegf-A-knockdown-MS-K clone [designated MS-K (A-KD)]. Proliferation and colony formation capacity of the MS-K (A-KD) cells in a semi-solid medium under low serum conditions was significantly lower than that of control MS-K (SCR) cells; however, the expression of vegf-receptor 1 (vegf-r-1) was not changed. Addition of the recombinant VEGF-A(165) partially restored the colony formation capacity of MS-K (A-KD) cells and caused the phosphorylation of VEGF-r-1 (Flt-1) in MS-K (Normal) cells. Furthermore, tumorigenicity of the vegf-r-1-knockdown-MS-K clone [designated MS-K (R1-KD)] had obviously delayed or strongly suppressed compared with the MS-K (Normal). These results indicate that Vascular endothelial growth factor-A, produced from MS-K, acts as a growth factor for MS-K cells itself and supports tumor formation in vivo by inducing the blood vessel formation.

    DOI: 10.1111/j.1365-2443.2011.01513.x

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  • Induction of anti-tumor cytotoxic T cell responses through PLGA-nanoparticle mediated antigen delivery 査読

    Zhiping Zhang, Songsak Tongchusak, Yo Mizukami, Yoon Joong Kang, Tetsuya Ioji, Maki Touma, Bruce Reinhold, Derin B. Keskin, Ellis L. Reinherz, Tetsuro Sasada

    BIOMATERIALS   32 ( 14 )   3666 - 3678   2011年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI LTD  

    Nanotechnology-based antigen delivery has been developing as a vaccine strategy due to its dose-sparing and prolonged antigen presentation features. In the current study, we examined the feasibility of nanoparticle (NP)-mediated delivery of antigenic peptides to efficiently induce cytotoxic T lymphocyte responses against tumor-associated self-antigens in C57BL/6 mouse models. The biodegradable poly(e, L-lactide-co-glycolide) nanoparticle (PLGA-NP) carrying murine melanoma antigenic peptides, hgp100(25-33) and TRP2(180-188), were prepared by double emulsion method. Efficient uptake of PLGA-NP by murine dendritic cells was shown in vitro and in vivo, using NP labeled with the fluorescent dye DiD. Intradermal injection of peptide-loaded PLGA-NP into mice induced antigen-specific T cell responses more strongly than the peptides mixed with Freund's adjuvant. More importantly, vaccination with PLGA-NP carrying both TRP2(180-188) and a toll-like receptor 4 agonist, monophosphoryl lipid A, significantly delayed growth of subcutaneously inoculated B16 melanoma cells in a prophylactic setting. Furthermore, the anti-tumor activity of NP-mediated peptide vaccination was significantly augmented by combined treatment with interferon-gamma, which might prevent tumor escape through up-regulation of MHC class I expression on tumor cells. Our findings demonstrate the feasibility of NP-mediated antigen delivery for cancer immunotherapy, in particular when immune escape mechanisms of tumor cells are blocked simultaneously. (C) 2011 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.biomaterials.2011.01.067

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  • Distinctive CD3 Heterodimeric Ectodomain Topologies Maximize Antigen-Triggered Activation of alpha beta T Cell Receptors 査読

    Sun Taek Kim, Maki Touma, Koh Takeuchi, Zhen-Yu J. Sun, Vibhuti P. Dave, Dietmar J. Kappes, Gerhard Wagner, Ellis L. Reinherz

    JOURNAL OF IMMUNOLOGY   185 ( 5 )   2951 - 2959   2010年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC IMMUNOLOGISTS  

    The alpha beta TCR has recently been suggested to function as an anisotropic mechanosensor during immune surveillance, converting mechanical energy into a biochemical signal upon specific peptide/MHC ligation of the alpha beta clonotype. The heterodimeric CD3 epsilon gamma and CD3 epsilon delta subunits, each composed of two Ig-like ectodomains, form unique side-to-side hydrophobic interfaces involving their paired G-strands, rigid connectors to their respective transmembrane segments. Those dimers are laterally disposed relative to the alpha beta heterodimer within the TCR complex. In this paper, using structure-guided mutational analysis, we investigate the functional consequences of a striking asymmetry in CD3 gamma and CD3 delta G-strand geometries impacting ectodomain shape. The uniquely kinked conformation of the CD3 gamma G-strand is crucial for maximizing Ag-triggered TCR activation and surface TCR assembly/expression, offering a geometry to accommodate juxtaposition of CD3 gamma and TCR beta ectodomains and foster quaternary change that cannot be replaced by the isologous CD3 delta subunit's extracellular region. TCR beta and CD3 subunit protein sequence analyses among Gnathostomata species show that the C beta FG loop and CD3 gamma subunit coevolved, consistent with this notion. Furthermore, restoration of T cell activation and development in CD3 gamma(-/-) mouse T lineage cells by interspecies replacement can be rationalized from structural insights on the topology of chimeric mouse/human CD3 epsilon delta dimers. Most importantly, our findings imply that CD3 gamma and CD3 delta evolved from a common precursor gene to optimize peptide/MHC-triggered alpha beta TCR activation. The Journal of Immunology, 2010, 185: 2951-2959.

    DOI: 10.4049/jimmunol.1000732

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  • The alpha beta T Cell Receptor Is an Anisotropic Mechanosensor 査読

    Sun Taek Kim, Koh Takeuchi, Zhen-Yu J. Sun, Maki Touma, Carlos E. Castro, Amr Fahmy, Matthew J. Lang, Gerhard Wagner, Ellis L. Reinherz

    JOURNAL OF BIOLOGICAL CHEMISTRY   284 ( 45 )   31028 - 31037   2009年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    Thymus-derived lymphocytes protect mammalian hosts against virus- or cancer-related cellular alterations through immune surveillance, eliminating diseased cells. In this process, T cell receptors (TCRs) mediate both recognition and T cell activation via their dimeric alpha beta, CD3 epsilon gamma, CD3 epsilon delta, and CD3 zeta zeta subunits using an unknown structural mechanism. Here, site-specific binding topology of anti-CD3 monoclonal antibodies (mAbs) and dynamic TCR quaternary change provide key clues. Agonist mAbs footprint to the membrane distal CD3 epsilon lobe that they approach diagonally, adjacent to the lever-like C beta FG loop that facilitates antigen (pMHC)-triggered activation. In contrast, a non-agonist mAb binds to the cleft between CD3 epsilon and CD3 gamma in a perpendicular mode and is stimulatory only subsequent to an external tangential but not a normal force (similar to 50 piconewtons) applied via optical tweezers. Specific pMHC but not irrelevant pMHC activates a T cell upon application of a similar force. These findings suggest that the TCR is an anisotropic mechanosensor, converting mechanical energy into a biochemical signal upon specific pMHC ligation during immune surveillance. Activating anti-CD3 mAbs mimic this force via their intrinsic binding mode. A common TCR quaternary change rather than conformational alterations can better facilitate structural signal initiation, given the vast array of TCRs and their specific pMHC ligands.

    DOI: 10.1074/jbc.M109.052712

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  • Functional role for I kappa BNS in T cell cytokine regulation as revealed by targeted gene disruption. 査読

    Touma M, Antonini V, Kumar M, Osborn SL, Bobenchik AM, Keskin DB, Connolly JE, Grusby MJ, Reinherz EL, Clayton LK

    Journal of immunology (Baltimore, Md. : 1950)   179 ( 3 )   1681 - 1692   2007年8月

  • Importance of the CD3 gamma ectodomain terminal beta-strand and membrane proximal stalk in thymic development and receptor assembly 査読

    Maki Touma, Zhen-Yu J. Sun, Linda K. Clayton, Wilfred E. Marissen, Ada M. Kruisbeek, Gerhard Wagner, Ellis L. Reinherz

    JOURNAL OF IMMUNOLOGY   178 ( 6 )   3668 - 3679   2007年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC IMMUNOLOGISTS  

    CD3 epsilon gamma and CD3 epsilon delta are noncovalent heterodimers; each consists of Ig-like extracellular domains associated side-to-side via paired terminal beta-strands that are linked to individual subunit membrane proximal stalk segments. CD3 epsilon, CD3 gamma, and CD3 delta stalks contain the RxCxxCxE motif. To investigate the functional importance of a CD3 stalk and terminal beta-strand, we created a CD3 gamma double mutant CD3 gamma(C82S/C85S) and a CD3 gamma beta-strand triple mutant CD3 gamma(Q76S/Y78A/Y79A) for use in retroviral transduction of lymphoid progenitors for comparison with CD3 gamma wt. Although both mutant CD3 gamma molecules reduced association with CD3 epsilon in CD3 epsilon gamma heterodimers, CD3 gamma(Q76S/Y78A/Y79A) abrogated surface TCR expression whereas CD3 gamma(C82S/C85S) did not. Furthermore, CD3 gamma(C82S/C85S) rescued thymic development in CD3 gamma(-/-) fetal thymic organ culture. However, the numbers of double-positive and single-positive thymocytes after CD3 gamma(C82S/C85S) transduction were significantly reduced despite surface pre-TCR and TCR expression comparable to that of CD3 gamma(-/-) thymocytes transduced in fetal thymic organ culture with a retrovirus harboring CD3 gamma wt cDNA. Furthermore, double-negative thymocyte development was perturbed with attenuated double-negative 3/double-negative 4 maturation and altered surface-expressed CD3 epsilon gamma, as evidenced by the loss of reactivity with CD3 gamma N terminus-specific antisera. Single histidine substitution of either CD3 gamma stalk cysteine failed to restore CD3 epsilon gamma association and conformation in transient COS-7 cell transfection studies. Thus, CD3 gamma(C82) and CD3 gamma(C85) residues likely are either reduced or form a tight intrachain disulfide loop rather than contribute to a metal coordination site in conjunction with CD3 epsilon(C80) and CD3 epsilon(C83). The implications of these results for CD3 epsilon gamma and TCR structure and signaling function are discussed.

    DOI: 10.4049/jimmunol.178.6.3668

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  • Adrenal participation in thymocyte death by anti-CD3 antibodies in vivo 査読

    Mitsuo Yoshida, Ken Gotoh, Masato Fujii, Hiroto Shimada, Maki Touma, Masamichi Hosono

    MICROBIOLOGY AND IMMUNOLOGY   51 ( 2 )   243 - 251   2007年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CENTER ACADEMIC PUBL JAPAN  

    The deletion of CD4- and CD8-double-positive (DP) cells in the thymus after treatment with anti-CD3 antibodies has long been considered as a useful model for clonal deletion during T cell development, although it was reported that DP cell death was not observed in neonates where self-tolerance should be developing. We dealt with the cellular basis of this enigmatic phenomenon in this report. Due to the similar susceptibility to the antibody-treatment in vitro between neonatal and adult thymocytes, critical factors may be outside rather than within the thymus. Indeed, newborn thymus lobes transplanted into recipients of different ages showed an increased susceptibility to the thymo-toxicity as the age of the recipient increased. The thymo-toxicity seems to be based on the adrenal function of glucocorticoid (GC) synthesis, because administration of an inhibitor of GC synthesis significantly reduced the DP cell death by the antibody-treatment. Finally, adrenalectomy completely prevented DP cell death by anti-CD3 antibodies in adult mice. Therefore, the thymocyte death by anti-CD3 antibodies in vivo may not be due to the T cell-receptor mediated selection in the thymus.

    DOI: 10.1111/j.1348-0421.2007.tb03896.x

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  • The TCR C beta FG loop regulates alpha beta T cell development. 査読

    Touma M, Chang HC, Sasada T, Handley M, Clayton LK, Reinherz EL

    Journal of immunology (Baltimore, Md. : 1950)   176 ( 11 )   6812 - 6823   2006年6月

  • Disparate peptide-dependent thymic selection outcomes in beta 2M-deficient mice versus TAP-1-deficient mice: implications for repertoire formation 査読

    T Sasada, Y Yang, CC Lai, M Touma, LK Clayton, JH Liu, E Parisini, JH Wang, EL Reinherz

    EUROPEAN JOURNAL OF IMMUNOLOGY   33 ( 2 )   368 - 380   2003年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-V C H VERLAG GMBH  

    Fetal thymic organ cultures of N15-transgenic RAG-2(-/-) H-2(b) mice on normal, beta-2 microglobulin (beta2M)(-/-) or transporter associated with antigen processing (TAP-1)(-/-) MHCI-deficient backgrounds were used to examine differentiation of thymocytes bearing a TCR specific for a viral peptide bound to H-2K(b). Strong agonists mediate negative selection in all mice whereas weak agonists are positively selecting in beta2M(-/-) mice but negatively selecting on TAP-1(-/-) or normal backgrounds. Very weak agonists and very weak antagonists are generally without effect in beta2M(-/-) mice yet foster differentiation in TAP-1(-/-) animals. The 20-40-fold reduction in beta2M(-/-) thymic H-2Kb surface expression suggests that the avidity of the TCR for peptide-MHCI accounts for these differences, consistent with effects of TCR density and individual thymic-peptide abundance in peptide-MHC complexes. TCR-self-MHC interaction dominates K-b-based selection, subtly modulated by peptides as revealed by X-ray crystallography.

    DOI: 10.1002/immu.200310011

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  • Involvement of the TCR C beta FG loop in thymic selection and T cell function 査読

    T Sasada, M Touma, HC Chang, LK Clayton, JH Wang, EL Reinherz

    JOURNAL OF EXPERIMENTAL MEDICINE   195 ( 11 )   1419 - 1431   2002年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ROCKEFELLER UNIV PRESS  

    The asymmetric disposition of T cell receptor (TCR) Cbeta and Calpha ectodomains creates a cavity with a side-wall formed by the rigid Cbeta FG loop. To investigate the significance of this conserved structure, we generated loop deletion (betaDeltaFG) and betawt transgenic (tg) mice using the TCR P subunit of the N15 CTL. N15betawt and N15betaDeltaFG H-2(b) animals have comparable numbers of thymocytes in S phase and manifest developmental progression through the CD4(-)CD8(-) double-negative (DN) compartment. N15betaDeltaFG facilitates transition from DN to CD4(+)8(+) double-positive (DP) thymocytes in recombinase activating gene (RAG)-2(-/-) mice, showing that pre-TCR function remains. N15betaDeltaFG animals possess similar totwofold more CD8(+) single-positive (SP) thymocytes and lymph node T cells, consistent with enhanced positive selection. As an altered Vet repertoire observed in N15betaDeltaFG mice may confound the deletion's effect, we crossed N15alphabeta TCR tg RAG-2(-/-) with N15betaDeltaFG tg RAG-2(-/-) H-2(b) mice to generate N15alphabeta RAG-2(-/-) and N15alphabeta.betaDeltaFG RAG-2(-/-) littermates. N15alphabeta.betaDeltaFG RAG-2(-/-) mice show an 8-10-fold increase in DP thymocytes due to reduced negative selection, as evidenced by diminished constitutive and cognate peptide-induced apoptosis. Compared with N15alphabeta, N15alphabeta.betaDeltaFG T cells respond poorly to cognate antigens and weak agonists. Thus, the Cbeta FG loop facilitates negative selection of thymocytes and activation of T cells.

    DOI: 10.1084/jem.20020119

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  • Peptide-induced negative selection of thymocytes activates transcription of an NF-kappa B inhibitor. 査読

    Fiorini E, Schmitz I, Marissen WE, Osborn SL, Touma M, Sasada T, Reche PA, Tibaldi EV, Hussey RE, Kruisbeek AM, Reinherz EL, Clayton LK

    Molecular cell   9 ( 3 )   637 - 648   2002年3月

  • Reversal of diabetes in mice by xenotransplantation of a bioartificial pancreas in a prevascularized subcutaneous site 査読

    WJ Wang, YJ Gu, Y Tabata, M Miyamoto, H Hori, N Nagata, M Touma, AN Balamurugan, Y Kawakami, M Nozawa, K Inoue

    TRANSPLANTATION   73 ( 1 )   122 - 129   2002年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Background. The subcutaneous site has been regarded as a potential site for a bioartificial pancreas. Transplantation of islets, encapsulated by the development of diverse biocompatible materials and structural designs, can reverse hyperglycemia in diabetic recipients.
    Methods. Approximately 750 Sprague-Dawley rat islets macroencapsulated in an agarose/poly (styrene sulfonic acid) mixed gel were implanted into a prevascularized subcutaneous site. The site was constructed by subcutaneous injection of basic fibroblast growth factor (bFGF) -impregnated gelatin microspheres in streptozotocin-induced C57BL/6 diabetic mice. Diabetic mice treated with bFGF-free gelatin microspheres and diabetic mice without any treatment undergoing the same subcutaneous transplantation were used as controls. After transplantation, non-fasting blood glucose, body weight, intraperitoneal glucose tolerance test, and histologic evaluations were processed.
    Results. All the recipients undergoing the subcutaneous xenograft returned to normoglycemia within I week after transplantation. Eight of 10 recipients in the bFGF+ group maintained normoglycemia for a period of 38-101 days and gradually gained increase of body weight. Two of 10 recipients became hyperglycemic again when the grafts were respectively retrieved at days 31 and 63. Intraperitoneal glucose tolerance tests at month I and 2 revealed significant ameliorated glucose tolerance but a tendency to reduced glucose tolerance when compared respectively with those of the streptozotocin-induced diabetic mice and normal mice. Histologic examination revealed that islets within the retrieved grafts at days 31 and 63 were viable and intact; no fibrotic overgrowth was present around the surface of grafts.
    Conclusions. A successfully prevascularized subcutaneous site could be constructed by a tissue bioengineering approach. Xenotransplantation of the agarose/poly (styrene sulfonic acid) mixed gel-based bioartificial pancreas in the prevascularized subcutaneous site could reverse diabetes in mice.

    DOI: 10.1097/00007890-200201150-00023

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MISC

  • 核内IκB分子IκB[NS]とB細胞分化・機能 (特集 B細胞)

    藤間 真紀

    臨床免疫・アレルギー科 = Clinical immunology & allergology   68 ( 2 )   129 - 135   2017年8月

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    記述言語:日本語   出版者・発行元:科学評論社  

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  • 免疫隔離膜を利用した膵島細胞移植 (〔2001年〕3月第5土曜特集 臓器移植の最前線) -- (基礎編--安全な移植技術の開発をめざして)

    藤間 真紀, 井上 一知

    医学のあゆみ   196 ( 13 )   929 - 933   2001年3月

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    記述言語:日本語   出版者・発行元:医歯薬出版  

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