Developmental mechanism of regulatory T cell-derived abnormal T cells identified by HAM

• Project/Area Number: 16K09702
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: St. Marianna University School of Medicine
• Principal Investigator: Sato Tomoo 聖マリアンナ医科大学, 医学研究科, 准教授 (30387063)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: HTLV-1 / Tax / 制御性T細胞 / HTLV-1関連脊髄症 / 神経内科学 / 神経病態免疫学

Outline of Final Research Achievements

Transdifferentiation of regulatory T cells (Treg) into Th1-like cells by HTLV-1 Tax is important for the pathogenesis of HTLV-1-associated myelopathy (HAM). However, the in vivo pathogenicity has not been clarified. Therefore, unlike previous Tax-expressing mice, we generated mice in which Tax expression was restricted to Treg and only one copy of Tax was expressed per cell. When expressed Tax homotypically, 28 of 28 mice (100%) died by 6 week-old, and all mice which expressed Tax heterogeneously had dermatitis and ulcers on the tail and pinna by 20 week-old. Thus, the in vivo pathogenicity of Treg-specific Tax expression was revealed.

Academic Significance and Societal Importance of the Research Achievements

本研究により、HTLV-1 Taxが発現する感染細胞の病原性が個体レベルにおいても重要であることが判明した。また、われわれが実施したHAM患者を対象とした抗CCR4抗体の早期臨床試験より、HTLV-1感染細胞を破壊することが、脊髄の炎症レベルを改善するだけでなく、臨床症状まで改善させる可能性が高く、これらを考え合わせると、HTLV-1感染細胞がHAMの病態に継続的に関与していることが明確となった。

Research Products

• [Journal Article] Development of reference material with assigned value for human T-cell leukemia virus type 1 quantitative PCR in Japan (2018)
  • Author(s): Kuramitsu M、Okuma K、Nakashima M、Sato T、Sasaki D、Hasegawa H、Umeki K、Kubota R、Sasada K、Sobata R、Matsumoto C、Kaneko N、Tezuka K、Matsuoka S、Utsunomiya A、Koh KR、Ogata M、Ishitsuka K、Taki M、Nosaka K、Uchimaru K、Iwanaga M、Sagara Y、Yamano Y、Okayama A、Miura K et al
  • Journal Title: Microbiology and Immunology Volume: 62 Issue: 10 Pages: 673-676
  • DOI: 10.1111/1348-0421.12644
  • NAID: 40021702629
  • Peer Reviewed / Open Access
• [Journal Article] Targeting human T‐lymphotropic virus type 1‐infected cells with an anti‐C‐C chemokine receptor 4 antibody in T‐lymphotropic virus type 1‐associated myelopathy. (2018)
  • Author(s): Sato T, Yamano Y.
  • Journal Title: Clin Exp Neuroimmunol Volume: 9(3) Issue: 3 Pages: 153-154
  • DOI: 10.1111/cen3.12467
  • Peer Reviewed / Open Access
• [Journal Article] HAMの疾患活動性分類と治療. (2018)
  • Author(s): 佐藤知雄
  • Journal Title: 医学のあゆみ Volume: 267(10) Pages: 756-760
• [Journal Article] HTLV-1関連脊髄症（HAM）の病態・診断・治療. (2018)
  • Author(s): 山野嘉久、山内淳司、新谷奈津美、八木下尚子、佐藤知雄.
  • Journal Title: 神経内科 Volume: 89(3) Pages: 297-303
• [Journal Article] Mogamulizumab (Anti-CCR4) in HTLV-1-Associated Myelopathy. (2018)
  • Author(s): Sato T, Coler-Reilly ALG, Yagishita N, Araya N, Inoue E, Furuta R, Watanabe T, Uchimaru K, Matsuoka M, Matsumoto N, Hasegawa Y, Yamano Y.
  • Journal Title: N Engl J Med. Volume: 378(6) Issue: 6 Pages: 529-538
  • DOI: 10.1056/nejmoa1704827
  • Peer Reviewed / Open Access
• [Journal Article] Effectiveness of Daily Prednisolone to Slow Progression of HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis: A Multi-Center Retrospective Cohort Study. (2017)
  • Author(s): Coler-Reilly ALG, Sato T, Matsuzaki T, Nakagawa M, Niino M, Nagai M, Nakamura T, Takenouchi N, Araya N, Yagishita N, Inoue E, Yamano Y.
  • Journal Title: Neurotherapeutics Volume: 14(4) Issue: 4 Pages: 1084-1094
  • DOI: 10.1007/s13311-017-0533-z
  • Peer Reviewed / Open Access
• [Journal Article] Proviral features of human T cell leukemia virus type 1 in carriers with indeterminate western blot analysis results. (2017)
  • Author(s): Kuramitsu M, Sekizuka T, Yamochi T, Firouzi S, Sato T, Umeki K, Sasaki D, Hasegawa H, Kubota R, Sobata R, Matsumoto C, Kaneko N, Momose H, Araki K, Saito M, Nosaka K, Utsunomiya A, Koh K, Ogata M, Uchimaru K, Iwanaga M, Sagara Y, Yamano Y, et al.
  • Journal Title: J Clin Microbiol. Volume: 55(9) Issue: 9 Pages: 2838-2849
  • DOI: 10.1128/jcm.00659-17
  • Peer Reviewed / Open Access
• [Journal Article] IL-10-mediated signals act as a switch for lymphoproliferation in Human T-cell leukemia virus type-1 infection by activating the STAT3 and IRF4 pathways. (2017)
  • Author(s): Sawada L, Nagano Y, Hasegawa A, Kanai H, Nogami K, Ito S, Sato T, Yamano Y, Tanaka Y, Masuda T, Kannagi M.
  • Journal Title: PLoS Pathog. Volume: 13(9) Issue: 9 Pages: e1006597-e1006597
  • DOI: 10.1371/journal.ppat.1006597
  • NAID: 120006825914
  • Peer Reviewed / Open Access
• [Journal Article] Developing novel treatments for HTLV-1-associated myelopathy (HAM) by investigating molecular pathomechanisms (2016)
  • Author(s): 新谷奈津美, 佐藤知雄, アリエラ・コラライリー, 八木下尚子, 山野嘉久.
  • Journal Title: Japanese Journal of Clinical Immunology Volume: 39 Issue: 3 Pages: 207-212
  • DOI: 10.2177/jsci.39.207
  • NAID: 130005157506
  • ISSN: 0911-4300, 1349-7413
  • Open Access
• [Journal Article] Nation-wide epidemiological study of Japanese patients with rare viral myelopathy using novel registration system (HAM-net). (2016)
  • Author(s): Coler-Reilly ALG, Yagishita N, Suzuki H, Sato T, Araya N, Inoue E, Takata A, Yamano Y.
  • Journal Title: Orphanet Journal of Rare Diseases Volume: 11(1) Issue: 1 Pages: 69-69
  • DOI: 10.1186/s13023-016-0451-x
  • Peer Reviewed / Open Access
• [Presentation] HAM患者に対する抗CCR4抗体製剤（モガムリズマブ）の安全性と有効性. (2018)
  • Author(s): 佐藤知雄、八木下尚子、新谷奈津美、井上永介、古田梨愛、渡邉俊樹、内丸薫、松岡雅雄、松本直樹、長谷川泰弘、山野嘉久.
  • Organizer: 第5回日本HTLV-1学会学術集会
• [Presentation] HAM患者レジストリ「HAMねっと」の運営. (2018)
  • Author(s): 八木下尚子、高橋克典、山内淳司、佐藤知雄、山野嘉久.
  • Organizer: 第5回日本HTLV-1学会学術集会
• [Presentation] 腎移植におけるHTLV-1感染症の危険性. (2018)
  • Author(s): 山内淳司、山野嘉久、佐藤知雄、八木下尚子、新谷奈津美、松岡雅雄、市丸直嗣、錦戸雅春、柴垣有吾、杉谷 篤、中村信之、三重野牧子、湯沢賢治.
  • Organizer: 第5回日本HTLV-1学会学術集会
• [Presentation] HTLV-1関連脊髄症に対する抗CCR4抗体製剤（モガムリズマブ）の医師主導治験. (2018)
  • Author(s): 佐藤知雄、八木下尚子、新谷奈津美、井上永介、古田梨愛、渡邉俊樹、内丸薫、松岡雅雄、松本直樹、長谷川泰弘、山野嘉久.
  • Organizer: 第30回日本神経免疫学会
• [Presentation] 希少疾患HAMに対する患者レジストリの活用. (2018)
  • Author(s): 八木下尚子、山内淳司、佐藤知雄、山野嘉久.
  • Organizer: 第30回日本神経免疫学会
• [Presentation] 腎移植後HTLV-1関連疾患の発症に関する全国調査. (2018)
  • Author(s): 山内淳司、山野嘉久、佐藤知雄、八木下尚子、新谷奈津美、松岡雅雄、市丸直嗣、錦戸雅春、柴垣有吾、杉谷 篤、中村信之、三重野牧子、湯沢賢治.
  • Organizer: 第30回日本神経免疫学会
• [Presentation] HTLV-1陽性臓器移植患者レジストリの構築. (2018)
  • Author(s): 山内淳司、山野嘉久、佐藤知雄、八木下尚子、新谷奈津美、松岡雅雄、市丸直嗣、錦戸雅春、柴垣有吾、杉谷 篤、中村信之、三重野牧子、湯沢賢治.
  • Organizer: 第54回日本移植学会
• [Presentation] HAM治療薬としての抗CCR4抗体製剤（モガムリズマブ）. (2018)
  • Author(s): 佐藤知雄、八木下尚子、新谷奈津美、井上永介、古田梨愛、渡邉俊樹、内丸薫、松岡雅雄、松本直樹、長谷川泰弘、山野嘉久.
  • Organizer: 第23回日本神経感染症学会総会・学術大会
• [Presentation] 腎移植患者のHTLV-1関連疾患発症に関する全国調査. (2018)
  • Author(s): 山内淳司、山野嘉久、佐藤知雄、八木下尚子、新谷奈津美、松岡雅雄、市丸直嗣、錦戸雅春、柴垣有吾、杉谷 篤、中村信之、三重野牧子、湯沢賢治.
  • Organizer: 第23回日本神経感染症学会総会・学術大会
• [Presentation] Prevalence, Incidence, and Evidence of High ATL Risk among HAM/TSP Patients (2017)
  • Author(s): Araya Natsumi, Sato Tomoo, Yagishita Naoko, Ariella Coler-Reilly, Uchimaru Kaoru, Yamano Yoshihisa
  • Organizer: The 18th International Conference on Human Retrovirology: HTLV and Related Viruses
  • Place of Presentation: 東京都千代田区 〔Grand Arc Hanzomon〕
  • Year and Date: 2017-03-07
  • Int'l Joint Research
• [Presentation] Daily Prednisolone Slows the Progression of HAM/TSP (2017)
  • Author(s): Ariella L. G. Coler-Reilly, Sato Tomoo, Matsuzaki Toshio, Nakagawa Masanori, Niino Masaaki, Nagai Masahiro, Nakamura Tatsufumi, Takenouchi Norihiro, Araya natsumi, Yagishita Naoko, Yamano Yoshihisa
  • Organizer: The 18th International Conference on Human Retrovirology: HTLV and Related Viruses
  • Place of Presentation: 東京都千代田区 〔Grand Arc Hanzomon〕
  • Year and Date: 2017-03-07
  • Int'l Joint Research
• [Presentation] Development of a New Assay for Quantification of HTLV-1 Proviral DNA (2017)
  • Author(s): Higashikuse Yuta, Nagai Go, Araya Natsumi, Yagishita Naoko, Sato Tomoo, Yamano yoshihisa
  • Organizer: The 18th International Conference on Human Retrovirology: HTLV and Related Viruses
  • Place of Presentation: 東京都千代田区 〔Grand Arc Hanzomon〕
  • Year and Date: 2017-03-07
  • Int'l Joint Research
• [Presentation] Progression Patterns of Osame's Motor Disability Score for HAM/TSP Patients (2017)
  • Author(s): Inoue Eisuke, Ariella Coler-Reilly, Araya Natsumi, Yagishita Naoko, Sato Tomoo, Takata Ayako, Yamano Yoshihisa
  • Organizer: The 18th International Conference on Human Retrovirology: HTLV and Related Viruses
  • Place of Presentation: 東京都千代田区 〔Grand Arc Hanzomon〕
  • Year and Date: 2017-03-07
  • Int'l Joint Research
• [Presentation] IL-10-mediated Signals as a Switch to Proliferation in HTLV-1-infected T Cells (2017)
  • Author(s): Leila Sawada, Yoshiko Nagano, Atsuhiko Hasegawa, Sayaka Ito, Tomoo Sato, Yoshihisa Yamano, Yuetsu Tanaka, Takao Masuda, Mari Kannagi
  • Organizer: The 18th International Conference on Human Retrovirology: HTLV and Related Viruses
  • Place of Presentation: 東京都千代田区 〔Grand Arc Hanzomon〕
  • Year and Date: 2017-03-07
  • Int'l Joint Research
• [Presentation] Investigation of Human Leukocyte Antigen on Human T-Lymphotropic Virus Type-1 Associated Myelopathy (HAM) by the Rare Disease Bank (2017)
  • Author(s): Mayako Tada, Yoshihisa Yamano, Tomoo Sato, Mitsuho Sasaki, Ryuichi Sakate, Akiko Hinomura, Makoto Hirata, Hidenori Tanaka, Hiroto Kojima, Arihiro Kohara, Akifumi Matsuyama
  • Organizer: The 18th International Conference on Human Retrovirology: HTLV and Related Viruses
  • Place of Presentation: 東京都千代田区 〔Grand Arc Hanzomon〕
  • Year and Date: 2017-03-07
  • Int'l Joint Research
• [Presentation] Effectiveness of Low-Dose Oral Prednisolone to Treat and Slow Progression of HAM/TSP: A Nationwide Prospective Cohort Study (2017)
  • Author(s): Sato Tomoo,Inoue Eisuke,Yagishita Naoko,Araya Natsumi,Takata Ayako,Yamano Yoshihisa
  • Organizer: The 18th International Conference on Human Retrovirology: HTLV and Related Viruses
  • Place of Presentation: 東京都千代田区 〔Grand Arc Hanzomon〕
  • Year and Date: 2017-03-07
  • Int'l Joint Research
• [Presentation] Patient Satisfaction Survey for HAM-net Registrants (2017)
  • Author(s): Suzuki Hiroko,Sato Kentaro,Kikuchi Takayuki,Kimura Miyuna,Arifuku Hirotaka,Komita Midori,Shimada Kanade,Seki Kurumi,Tachibana Marika,Yagishita Naoko,Ariella Coler-Reilly,Sato Tomoo,Araya Natsumi,Ishikawa Miho,Koike Mikako,Saito Yumi,Takata Ayako,Yamano Yoshihisa
  • Organizer: The 18th International Conference on Human Retrovirology: HTLV and Related Viruses
  • Place of Presentation: 東京都千代田区 〔Grand Arc Hanzomon〕
  • Year and Date: 2017-03-07
  • Int'l Joint Research
• [Presentation] Biomarkers for Predicting Treatment Response in Patients with HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) (2017)
  • Author(s): Tamaki Keiko , Sato Tomoo , Ariella Coler-Reilly, Inoue Eisuke , Tsugawa Jun , Yamano Yoshihisa , Tsuboi Yoshio
  • Organizer: The 18th International Conference on Human Retrovirology: HTLV and Related Viruses
  • Place of Presentation: 東京都千代田区 〔Grand Arc Hanzomon〕
  • Year and Date: 2017-03-07
  • Int'l Joint Research
• [Presentation] Comparative Transcriptome Analysis of HTLV-1-infected Cells and ATL Cells (2017)
  • Author(s): Yamagishi Makoto, Nakano Kazumi, Fujikawa Dai, Kobayashi Seiichiro, Araya Natsumi, Sato Tomoo, Yagishita Naoko, Iwanaga Masako, Utsunomiya Atae, Tanaka Yuetsu , Yamano Yoshihisa, Watanabe Toshiki, Uchimaru Kaoru
  • Organizer: The 18th International Conference on Human Retrovirology: HTLV and Related Viruses
  • Place of Presentation: 東京都千代田区 〔Grand Arc Hanzomon〕
  • Year and Date: 2017-03-07
  • Int'l Joint Research
• [Presentation] A New Index Describing Urinary Dysfunction in Patients with Human T-lymphotropic Virus Type 1-associated Myelopathy (2017)
  • Author(s): Yamakawa Natsuko, Amano Saaya, Kawakami Hitomi, Yamashita Hitomi, Yagishita Naoko, Araya Natsumi, Sato Tomoo, Takata Ayako, Matsuo Tomohiro, Yamano Yoshihisa
  • Organizer: The 18th International Conference on Human Retrovirology: HTLV and Related Viruses
  • Place of Presentation: 東京都千代田区 〔Grand Arc Hanzomon〕
  • Year and Date: 2017-03-07
  • Int'l Joint Research
• [Presentation] Phase 1/2a study of Mogamulizumab, an anti-CCR4 monoclonal antibody, in patients with HTLV-1-associated myelopathy (HAM/TSP). (2017)
  • Author(s): Yamano Y, Sato T, A. Coler-Reilly, Yanagisawa N, Araya N, Inoue E, Furuta R, Watanabe T, Uchimaru K, Matsuoka M, Matsumoto N, Hasegawa Y.
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] 臨床経過とバイオマーカーに基づくＨＡＭの疾患活動性分類基準の提案. (2017)
  • Author(s): 長谷川大輔, 八木下尚子, 井上永介, 新谷奈津美, 髙田 礼子, 長谷川泰弘, 佐藤知雄, 山野嘉久.
  • Organizer: 第４回日本ＨＴＬＶ－１学会学術集会
• [Presentation] Potential contribution of IL-10-mediated STAT3 signals to push HTLV-1-infected cells towards proliferation by enhancing survivin and IRF4 expression. (2017)
  • Author(s): Sawada L, Nagano Y, Hasegawa A, Ito S, Sato T, Yamano Y, Tanaka Y, Masuda T, Kannagi M.
  • Organizer: 第４回日本ＨＴＬＶ－１学会学術集会
• [Presentation] ＨＴＬＶ－１関連脊髄症（ＨＡＭ）の新たな運動障害重症度評価指標の提案. (2017)
  • Author(s): 八木下尚子, 佐藤知雄, 長谷川大輔, 新谷奈津美, 井上永介, 高田礼子, 山野嘉久.
  • Organizer: 第４回日本ＨＴＬＶ－１学会学術集会
• [Presentation] ＨＡＭ患者レジストリを活用した低用量経口プレドニゾロン維持療法の有効性と安全性に関する検討. (2017)
  • Author(s): 佐藤知雄, 井上永介, 八木下尚子, 新谷奈津美, 長谷川大輔, 高田礼子, 山野嘉久.
  • Organizer: 第４回日本ＨＴＬＶ－１学会学術集会
• [Presentation] IL-10はsurvivinとIRF4の誘導を介してHTLV-1感染細胞の増殖を促進する (2016)
  • Author(s): Sawada L, 永野佳子, 長谷川温彦, 金井光, 佐藤知雄, 山野嘉久, 田中勇悦, 神奈木真理.
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 神奈川（横浜市西区）〔パシフィコ横浜〕
  • Year and Date: 2016-10-06
• [Presentation] HAM発症から診断までの期間における納の運動障害重症度の経時推移の解析 (2016)
  • Author(s): 井上永介、Ariella Coler-Reilly、新谷奈津美、八木下尚子、佐藤知雄、高田礼子、山野嘉久
  • Organizer: 第3回日本HTLV-1学会学術集会
  • Place of Presentation: 鹿児島県（鹿児島市）〔鹿児島県市町村自治会館〕
  • Year and Date: 2016-08-26
• [Presentation] HAM患者に対する経口ステロイド維持療法の長期的効果 (2016)
  • Author(s): 佐藤知雄、Ariella Coler-Reilly、新谷奈津美、八木下尚子、中村龍文、永井将弘、新野正明、竹ノ内徳博、中川正法、松崎敏男、山野嘉久
  • Organizer: 第3回日本HTLV-1学会学術集会
  • Place of Presentation: 鹿児島県（鹿児島市）〔鹿児島県市町村自治会館〕
  • Year and Date: 2016-08-26
• [Presentation] HTLV-1関連脊髄症（HAM）におけるHAS-Flow法を用いたATL発症高危険度患者の予測 (2016)
  • Author(s): 新谷奈津美、佐藤知雄、八木下尚子、高橋克典、内丸薫、山野嘉久
  • Organizer: 第3回日本HTLV-1学会学術集会
  • Place of Presentation: 鹿児島県（鹿児島市）〔鹿児島県市町村自治会館〕
  • Year and Date: 2016-08-26
• [Presentation] HAM患者における治療効果を予測するバイオマーカーの検討 (2016)
  • Author(s): 玉木慶子、佐藤知雄、津川潤、山野嘉久、坪井義夫
  • Organizer: 第3回日本HTLV-1学会学術集会
  • Place of Presentation: 鹿児島県（鹿児島市）〔鹿児島県市町村自治会館〕
  • Year and Date: 2016-08-26
• [Remarks] 聖マリアンナ医科大学 難病治療研究センター
  • URL: http://nanchiken.jp/
• [Remarks] 聖マリアンナ医科大学難病治療研究センター
  • URL: http://nanchiken.jp/
• [Remarks] http://nanchiken.jp/byouin/