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医学部 医学科 感染症学講座免疫学分野 |
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Mitoma S., Carr B.V., Harvey Y., Moffat K., Sekiguchi S., Charleston B., Norimine J., Seago J.
Immunology 164 ( 2 ) 266 - 278 2021年10月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Immunology
Foot-and-mouth disease (FMD) is a highly contagious, economically devastating disease of cloven-hooved animals. The development of long-lasting effective FMD vaccines would greatly benefit the global FMD control programme. Deep analysis of adaptive immunity in cattle vaccinated against FMD is technically challenging due to the lack of species-specific tools. In this study, we aimed to identify CD4+ T-cell epitopes in the FMD virus (FMDV) capsid and to phenotype the CD4+ T cells that recognize them using bovine major histocompatibility complex (BoLA) class II tetramer. A BoLA class II tetramer based on the DRA/DRB3*020:02 allele and FMDV antigen-stimulated PBMCs from bovine vaccinates were used to successfully identify four epitopes in the FMDV capsid, three of which have not been previously reported; two epitopes were identified in the structural protein VP1, one in VP3 and one in VP4. Specificity of the three novel epitopes was confirmed by proliferation assay. All epitope-expanded T-cell populations produced IFN-γ in vitro, indicating a long-lasting Th1 cell phenotype after FMD vaccination. VP3-specific CD4+ T cells exhibited the highest frequency amongst the identified epitopes, comprising >0·004% of the CD4+ T-cell population. CD45RO+CCR7+ defined central memory CD4+ T-cell subpopulations were present in higher frequency in FMDV-specific CD4+ T-cell populations from FMD-vaccinated cattle ex vivo. This indicates an important role in maintaining cell adaptive immunity after FMD vaccination. Notably, FMDV epitope-loaded tetramers detected the presence of FMDV-specific CD4+ T cells in bovine PBMC more than four years after vaccination. This work contributes to our understanding of vaccine efficacy.
DOI： 10.1111/imm.13367
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Tahira Y., Shide K., Kameda T., Uchida T., Kamiunten A., Akizuki K., Kubuki Y., Karasawa M., Ikeda R., Matsumoto K., Bai J., Terashima M., Kato K., Uto T., Fukaya T., Mitoma S., Sato K., Uehira Y., Ueno H., Sashida G., Yamaguchi H., Shimoda K.
Blood Neoplasia 2 ( 3 ) 100087 - 100087 2025年8月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Blood Neoplasia
Interferon-α (IFN-α) exhibits antiviral and antiproliferative effects on normal and neoplastic cells. Intracellular signaling of IFN-α is mediated by tyrosine kinase 2 (TYK2) and janus kinase 1 (JAK1), followed by signal transducers and activators of transcription (STATs). TYK2 is redundant for the antiviral effect of IFN-α; however, the requirements for antiproliferative effects are unknown. We assessed the role of TYK2 in the effects of IFN-α in myeloproliferative neoplasm (MPN) model mice. Jak2V617F transgenic mice develop MPNs resembling human primary myelofibrosis, and ropeginterferon-α-2b ameliorated their features. However, these IFN-α effects were absent in Jak2V617F;Tyk2<sup>−/−</sup> mice. In mixed wild-type (WT)/Jak2V617F chimeric mice, IFN-α treatment induces Jak2V617F hematopoietic stem cells (HSCs) to enter the cell cycle and skew their differentiation into the megakaryocyte lineage, decreasing the number of Jak2V617F HSCs. The effects of IFN-α on Jak2V617F HSCs were not observed in mixed WT/Jak2V617F;Tyk2<sup>−/−</sup> mice, indicating that TYK2 is essential for the effects of IFN-α on both Jak2V617F progenitors and HSCs. The mechanism of IFN-α in Jak2V617F HSCs and progenitors differed: genes regulating the cell cycle were enriched in IFN-α–stimulated Jak2V617F HSCs, but not in Jak2V617F progenitors; genes regulating antiproliferation were enriched in IFN-α–stimulated Jak2V617F progenitors but not in Jak2V617F HSCs. The major IFN-α signaling molecule activated by JAKs is STAT1, which is essential for the antiviral effect. Most effects of IFN-α on Jak2V617F cells were preserved in Jak2V617F;Stat1<sup>−/−</sup> mice but to a moderate degree compared with Jak2V617F mice. Our study reveals essential roles of TYK2 for the preferential suppressive effect of IFN-α on Jak2V617F progenitors and HSCs.
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Selectivity of bovine interleukin-2 mutein stimulation on bovine peripheral blood mononuclear cells 査読あり
Mitoma S., Uto T., Fukaya T., Tominaga M., Sekiguchi S., Sato K., Norimine J.
Ｔｈｅ Ｊｏｕｒｎａｌ ｏｆ Ｖｅｔｅｒｉｎａｒｙ Ｍｅｄｉｃａｌ Ｓｃｉｅｎｃｅ 87 ( 7 ) 781 - 790 2025年
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：公益社団法人 日本獣医学会
Delivery of engineered interleukin-2 (IL-2) variants (muteins) is thought to be a promising cancer therapy in humans and mice. Our previous study indicated that bovine IL-2 (boIL-2) has a great potential to elicit NK cell activity for which distribution of IL-2 receptors on the target cell surface influences signal transduction. We developed nine boIL-2 muteins and examined the influence of the muteins on bovine peripheral blood mononuclear cells in vitro. On bovine peripheral mononuclear cells, NK cells strongly expressed CD122, followed by CD8<sup>+</sup> T cells, while CD4<sup>+</sup> T cells and γδ T cells did not show significant CD122 expression. All boIL-2 muteins showed decreasing in binding to boIL-2 receptor α, CD25, while maintaining their ability to bind to boIL-2 receptor βγ, CD122/CD132, heterodimer. The mutein F44A and E63A suppressed CD4<sup>+</sup> T cell expansion but maintained the NK cell expansion. These results indicate that boIL-2 muteins can alter immunological outcomes and may be used for clinical intervention for a disease progression.
DOI： 10.1292/jvms.24-0470
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Lkham-Erdene B., Choijookhuu N., Kubota T., Uto T., Mitoma S., Shirouzu S., Ishizuka T., Kai K., Higuchi K., Aung K.M., Batmunkh J.E., Sato K., Hishikawa Y.
Ａｃｔａ Ｈｉｓｔｏｃｈｅｍｉｃａ ｅｔ Ｃｙｔｏｃｈｅｍｉｃａ 57 ( 5 ) 175 - 188 2024年10月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：日本組織細胞化学会
Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming a major health problem worldwide. Liver regeneration is crucial for restoring liver function, and is regulated by extraordinary complex process, involving numerous factors under both physiologic and pathologic conditions. Sphingosine-1-phosphate (S1P), a bioactive sphingolipid synthesized by sphingosine kinase 1 (SphK1), plays an important role in liver function through S1P receptors (S1PRs)-expressing cells. In this study, we investigated the effect of lipid overload on hepatocyte proliferation in a mouse hepatic steatosis model induced by feeding a methionine-and choline-deficient (MCD) diet. After 50% partial hepatectomy (PHx), liver tissues were sampled at various timepoints and then analyzed by immunohistochemistry, oil Red-O staining, quantitative-polymerase chain reaction (qPCR), and flow cytometry. In mice fed the MCD-diet, significantly exacerbated hepatic steatosis and accelerated liver regeneration were observed. After PHx, hepatocyte proliferation peaked at 48 and 36 hr in the liver of chow-and MCD-diet fed mice, respectively. By contrast, increased expression of S1PR2 was observed in hepatic neutrophils and macrophages of MCD-diet fed mice. Flow cytome-try and qPCR experiments demonstrated that levels of HGF and FGF2 released by neutrophils and macrophages were significantly higher in MCD-diet fed mice. In conclusion, hepatic lipid overload recruits Kupffer cells and neutrophils that release HGF and FGF2 via SphK1/S1PR2 activation to accelerate hepatocyte proliferation.
DOI： 10.1267/ahc.24-00046
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Tominaga M., Uto T., Fukaya T., Mitoma S., Riethmacher D., Umekita K., Yamashita Y., Sato K.
Frontiers in Immunology 15 1200461 - 1200461 2024年
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Frontiers in Immunology
Dendritic cells (DCs) are known as unique professional antigen (Ag)-presenting cells (APCs) to prime naïve T cells for the initiation of adaptive immunity. While DCs are believed to play a pivotal role in generating anti-tumor T-cell responses, the importance of DCs in the protection from the progression of tumors remains elusive. Here, we show how the constitutive deficiency of CD11chi DCs influences the progression of tumors with the use of binary transgenic mice with constitutive loss of CD11chi DCs. Constitutive loss of CD11chi DCs not only enhances the progression of tumors but also reduces the responses of Ag-specific T cells. Furthermore, the congenital deficiency of CD11chi DCs generates the immunosuppressive tumor microenvironment (TME) that correlates with the marked accumulation of myeloid-derived suppressor cells (MDSCs) and the prominent productions of immunosuppressive mediators. Thus, our findings suggest that CD11chi DCs are crucial for generating anti-tumor T-cell responses and immunogenic TME to suppress the development of tumors.
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樹状細胞のはたらき⑧樹状細胞を標的とした免疫チェックポイント阻害療法
宇都倫史, 深谷知宏, 三苫修也, 佐藤克明
Veterinary Immunology for Practitioners ( 37 ) 26 - 31 2025年1月
掲載種別：速報，短報，研究ノート等（学術雑誌）
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樹状細胞のはたらき⑦がん免疫応答における通常型樹状細胞の役割
宇都倫史, 深谷知宏, 三苫修也, 佐藤克明
Veterinary Immunology for Practitioners ( 36 ) 46 - 47 2024年10月
掲載種別：速報，短報，研究ノート等（学術雑誌）
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宮崎県における牛ウイルス性下痢の積極的疫学調査と分離株の遺伝子系統解析
野津 昂亮, 龍 千香, Ul Hakim Bin Rahmat Luqman, Ullah Shakir, 植木 萌葉, 三苫 修也, 乗峰 潤三, 青木 博史, 亀山 健一郎, 迫田 義博, 関口 敏
獣医疫学雑誌 28 ( 1 ) 20 - 21 2024年7月
記述言語：日本語 掲載種別：速報，短報，研究ノート等（学術雑誌） 出版者・発行元：獣医疫学会
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樹状細胞のはたらき⑥アレルギー疾患に対する舌下免疫療法の防御効果における樹状細胞の役割.
深谷知宏, 宇都倫史, 三苫修也, 佐藤克明
Veterinary Immunology for Practitioners ( 35 ) 2024年
記述言語：日本語 掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
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牛伝染性リンパ腫の抵抗性判別 招待あり
関口敏, 三苫修也, 野津昴亮
臨床獣医 42 ( 6 ) 2024年
記述言語：日本語 掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
講演・口頭発表等 【 表示 ／ 非表示 】
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高度免疫不全マウスを用いた牛伝染性リンパ腫担がんマウスモデル及び牛免疫細胞移植マウスモデルの作製と有用性の検討
三苫 修也, 宇都 倫史, 深谷 知宏, 冨永 萌, 関口 敏, 佐藤 克明
第167回日本獣医学会学術集会 2024年9月10日
開催年月日： 2024年9月10日 - 2024年9月13日
会議種別：口頭発表（一般）
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ルシフェラーゼ融合蛋白結合抗体捕捉法を用いた抗牛伝染性リンパ腫ウイルス抗体検出法の開発
内田 大紀, 三苫 修也, 野津 昂亮, 関口 敏
第167回日本獣医学会学術集会 2024年9月10日
開催年月日： 2024年9月10日 - 2024年9月13日
会議種別：口頭発表（一般）
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Selective cell stimulation with bovine interleukin-2 mutein and the distribution of bovine CD122 on the peripheral lymphocytes
Shuya Mitoma, Tomofumi Uto, Tomohiro Fukaya, Moe Tominaga, Katsuaki Sato, Junzo Norimine
第52回日本免疫学会学術集会 2024年1月17日
開催年月日： 2024年1月17日 - 2024年1月19日
記述言語：英語 会議種別：ポスター発表
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外部導入牛における牛白血病ウイルス感染の定量的リスク分析
野津昂亮, WIRATSUDAKUL Anuwat, 三苫修也, 乗峰潤三, 関口敏
日本産業動物獣医学会(九州)・日本小動物獣医学会(九州)・日本獣医公衆衛生学会(九州) 2017年
開催年月日： 2017年
会議種別：口頭発表（一般）
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宮崎県における肉用牛生産者を対象とした牛白血病対策に関する意識調査
森山楓栞, 耕野拓一, 窪田さと子, 三苫修也, 目堅博久, 乗峰潤三, 関口敏
日本産業動物獣医学会(九州)・日本小動物獣医学会(九州)・日本獣医公衆衛生学会(九州) 2017年
開催年月日： 2017年
会議種別：口頭発表（一般）
科研費（文科省・学振・厚労省）獲得実績 【 表示 ／ 非表示 】
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牛伝染性リンパ腫ウイルス感染症に対するNK細胞選択的活性による防御免疫効果
研究課題/領域番号：22K15013 2022年04月 - 2025年03月
日本学術振興会 科学研究費基金 若手研究
三苫 修也
担当区分：研究代表者
受託研究受入実績 【 表示 ／ 非表示 】
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新規ヒト樹状細胞発現免疫チェックポイント分子を標的とした免疫チェックポイント阻害剤に関する研究開発
2025年04月 - 2026年03月
国立研究開発法人日本医療研究開発機構 一般受託研究
佐藤 克明、宇都 倫史、深谷 知宏、三苫 修也
担当区分：研究分担者 受託研究区分：一般受託研究
寄附金・講座・研究部門 【 表示 ／ 非表示 】
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感染症学講座免疫学分野研究奨学金(ﾆｯﾎﾟﾝﾊﾑ食の未来財団)
寄附者名称：公益財団法人ﾆｯﾎﾟﾝﾊﾑ食の未来財団 2024年02月