Novel treatment of autoimmune diseases using myeloid-derived suppressor cell

• Project/Area Number: 16K19599
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Collagenous pathology/Allergology
• Research Institution: Kobe University
• Principal Investigator: Nishimura Keisuke 神戸大学, 医学研究科, 医学研究員 (20771497)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
• Keywords: 関節リウマチ / 骨髄由来抑制細胞 / 代謝 / 骨髄由来抑制細胞（MDSC） / 骨髄由来抑制細胞 (MDSC) / 免疫学

Outline of Final Research Achievements

Glutamine metabolism and the mechanistic mTOR pathway are activated cooperatively in the differentiation and activation of inflammatory immune cells. This study investigated how inhibiting both glutamine metabolism with DON and mTOR with rapamycin affects immune cells and the arthritis in a mouse model. We revealed that rapamycin and DON additively suppressed CD4+ T cell proliferation, and both of them inhibited Th17 cell differentiation. While DON inhibited the differentiation of dendritic cells and macrophages and facilitated that of Ly6G+ granulocytic (G)-MDSCs more strongly than did rapamycin, G-MDSCs treated with rapamycin but not DON suppressed CD4+ T cell proliferation in vitro. The combination of rapamycin and DON significantly suppressed the arthritis in SKG mice more strongly than did each monotherapy in vivo. The numbers of CD4+ T and Th17 cells in the spleen were lowest in mice treated with the combination therapy.

Academic Significance and Societal Importance of the Research Achievements

関節リウマチ治療は生物学的製剤やJAK阻害剤の登場により、治療成績は格段に改善したが、2～3割の関節リウマチ患者では寛解が得られていない。我々はmTOR阻害剤のラパマイシンとグルタミン代謝阻害剤DONの併用療法で関節リウマチモデルであるSKGマウスの関節炎抑制効果を示すことができた。機序としてはCD4陽性T細胞の増殖とTh17細胞の分化を抑制することである。mTORおよびグルタミン代謝を同時に阻害することによる新しい関節リウマチの治療戦略を示すことができた。

Research Products

• [Journal Article] Shoulder ultrasound and serum lactate dehydrogenase predict inadequate response to glucocorticoid treatment in patients with polymyalgia rheumatica. (2020)
  • Author(s): Ayano M, Arinobu Y, Tsukamoto H, Ota SI, Misaki K, Nishimura K, Kimoto Y, Mitoma H, Akahoshi M, Akashi K, Horiuchi T, Niiro H.
  • Journal Title: Rheumatology International Volume: - Issue: 7 Pages: 1101-1109
  • DOI: 10.1007/s00296-020-04512-9
  • Peer Reviewed / Open Access
• [Journal Article] Additive effects of inhibiting both mTOR and glutamine metabolism on the arthritis in SKG mice (2019)
  • Author(s): Ueda Yo、Saegusa Jun、Okano Takaichi、Sendo Sho、Yamada Hirotaka、Nishimura Keisuke、Morinobu Akio
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 6374-6374
  • DOI: 10.1038/s41598-019-42932-1
  • NAID: 120006624233
  • Peer Reviewed / Open Access
• [Journal Article] Tofacitinib facilitates the expansion of myeloid-derived suppressor cells and ameliorates interstitial lung disease in SKG mice. (2019)
  • Author(s): Sendo S, Saegusa J, Yamada H, Nishimura K, Morinobu A.
  • Journal Title: Arthritis Research Therapy Volume: 6 Issue: 1 Pages: 184-184
  • DOI: 10.1186/s13075-019-1963-2
  • NAID: 120006713587
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of Plasma Exchange in Anti‐neutrophil Cytoplasmic Antibody‐associated Vasculitis (2019)
  • Author(s): Nishimura Keisuke、Waki Daisuke、Kadoba Keiichiro、Mukoyama Hiroki、Yokota Toshihiko、Murabe Hiroyuki
  • Journal Title: Therapeutic Apheresis and Dialysis Volume: 29 Issue: 3 Pages: 248-252
  • DOI: 10.1111/1744-9987.12828
  • Peer Reviewed
• [Journal Article] Genetic and clinical prediction models for the efficacy and hepatotoxicity of methotrexate in patients with rheumatoid arthritis: a multicenter cohort study (2019)
  • Author(s): Onishi Akira、Kamitsuji Shigeo、Nishida Miwa、Uemura Yuko、Takahashi Miho、Saito Toshiharu、Yoshida Yuichiro、Kobayashi Masaki、Kawate Mizuho、Nishimura Keisuke、Misaki Kenta、Nobuhara Yumiko、Nakazawa Takashi、Hatachi Saori、Tsuji Goh、Morinobu Akio、Kumagai Shunichi
  • Journal Title: The Pharmacogenomics Journal Volume: - Issue: 3 Pages: 433-442
  • DOI: 10.1038/s41397-019-0134-9
  • Peer Reviewed
• [Journal Article] Radiographic fibrosis score predicts survival in systemic sclerosis-associated interstitial lung disease. (2018)
  • Author(s): Takei R, Arita M, Kumagai S, Ito Y, Tokioka F, Koyama T, Saito R, Nishimura K, Tokumasu H, Ishida T.
  • Journal Title: Respirology Volume: 23 Issue: 4 Pages: 385-391
  • DOI: 10.1111/resp.13175
  • Peer Reviewed
• [Journal Article] Radiological fibrosis score is strongly associated with worse survival in rheumatoid arthritis-related interstitial lung disease (2018)
  • Author(s): Ito Yuhei、Arita Machiko、Kumagai Shogo、Takei Reoto、Noyama Maki、Tokioka Fumiaki、Nishimura Keisuke、Koyama Takashi、Tachibana Hiromasa、Ishida Tadashi
  • Journal Title: Modern Rheumatology Volume: 13 Issue: 1 Pages: 1-7
  • DOI: 10.1080/14397595.2018.1442170
  • Peer Reviewed
• [Journal Article] Serological and morphological prognostic factors in patients with interstitial pneumonia with autoimmune features. (2017)
  • Author(s): Ito Y, Arita M, Kumagai S, Takei R, Noyama M, Tokioka F, Nishimura K, Koyama T, Notohara K, Ishida T.
  • Journal Title: BMC Pulm Med Volume: 14 Issue: 1
  • DOI: 10.1186/s12890-017-0453-z
  • Peer Reviewed
• [Journal Article] 3-bromopyruvate ameliorate autoimmune arthritis by modulating Th17/Treg cell differentiation and suppressing dendritic cell activation. (2017)
  • Author(s): Okano T, Saegusa J, Nishimura K, Takahashi S, Sendo S, Ueda Y, Morinobu A
  • Journal Title: Scientific Reports Volume: 7
  • NAID: 120006624239
  • Peer Reviewed
• [Journal Article] Very high frequency of fragility fractures associated with high-dose glucocorticoids in postmenopausal women: A retrospective study. (2017)
  • Author(s): Kageyama G, Okano T, Yamamoto Y, Nishimura K, Sugiyama D, Saegusa J, Tsuji G, Kumagai S, Morinobu A.
  • Journal Title: Bone Reports Volume: 6 Pages: 3-8
  • DOI: 10.1016/j.bonr.2016.11.003
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Knockout of endothelin type B receptor signaling attenuates bleomycin-induced skin sclerosis in mice. (2016)
  • Author(s): Akashi K, Saegusa J, Sendo S, Nishimura K, Okano T, Yagi K, Yanagisawa M, Emoto N, Morinobu A.
  • Journal Title: Arthritis Res Ther. Volume: 18 Issue: 1 Pages: 113-113
  • DOI: 10.1186/s13075-016-1011-4
  • NAID: 120007135444
  • Peer Reviewed / Open Access
• [Journal Article] Expression and Functions of Immediate Early Response Gene X-1 (IEX-1) in Rheumatoid Arthritis Synovial Fibroblasts. (2016)
  • Author(s): Morinobu A, Tanaka S, Nishimura K, Takahashi S, Kageyama G, Miura Y, Kurosaka M, Saegusa J, Kumagai S.
  • Journal Title: PLoS One Volume: 11 Issue: 10 Pages: e0164350-e0164350
  • DOI: 10.1371/journal.pone.0164350
  • NAID: 120005898575
  • Peer Reviewed / Open Access
• [Presentation] PREDICTORS OF RELAPSE OF IGG4-RELATED DISEASE AFTER INDUCTION THERAPY: A RETROSPECTIVE STUDY (2019)
  • Author(s): Tomohiro Yoshida, Keisuke Nishimura, Kaoru Mizukawa, Keiichiro Kadoba, Hiroki Mukoyama, Daisuke Waki, Toshihiko Yokota, Hiroyuki Murabe
  • Organizer: Annual European Congress of Rheumatology
  • Int'l Joint Research
• [Presentation] IgG4関連疾患の臨床所見と顎下腺超音波shear wave elastographyの関連 (2019)
  • Author(s): 西村啓佑、佐原朗子、水川薫、門場啓一郎、吉田知宏、脇大輔、村部浩之、横田敏彦
  • Organizer: 第47回 日本臨床免疫学会総会
• [Presentation] Shear Wave Elastography in the Evaluation of Submandibular Gland Characteristics in IgG4-Related Disease (2018)
  • Author(s): Keisuke Nishimura, Keiichiro kadoba, Hiroki Mukoyama, Rintaro Saito, Daisuke Waki, Toshihiko Yokota
  • Organizer: American College of Rheumatology 2019
  • Int'l Joint Research
• [Presentation] The Efficacy of Denosumab for Prevention of Osteoporotic Fractures in Patients with Connective Tissue Diseases Receiving Very High Doses of Glucocorticoid (2018)
  • Author(s): keiichiro Kadoba, Keisuke Nishimura, Hiroki Mukoyama, Rintaro Saito, Daisuke Waki, Toshihiko Yokota
  • Organizer: American College of Rheumatology 2019
  • Int'l Joint Research
• [Presentation] ANCA関連血管炎に対する血漿交換療法の有用性 (2018)
  • Author(s): 西村啓佑、脇大輔、門場啓一郎、向山宙希、横田敏彦
  • Organizer: 第39回 日本アフェレシス学会
• [Presentation] IgG4関連疾患の顎下腺病変における超音波shear wave elastographyの有用性 (2018)
  • Author(s): 西村啓佑, 脇大輔, 門場啓一郎, 向山宙希, 横田敏彦
  • Organizer: 第46回 日本臨床免疫学会総会
• [Presentation] Inhibition of the mTOR Pathway and Glutaminolysis Facilitates the Expansion of Myeloid-Derived Suppressor Cells and Synergistically Ameliorates Arthritis in SKG Mice. (2017)
  • Author(s): Yo Ueda, Jun Saegusa, Takaichi Okano, Sho Sendo, Keisuke Nishimura, Hirotaka Yamada, Soshi Takahashi, Kengo Akashi, Akio Morinobu
  • Organizer: 第46回日本免疫学会総会・学術集会
• [Presentation] 3-bromopyruvate ameliorate autoimmune arthritis by modulating Th17/Treg cell differentiation and suppressing dendritic cell activation (2017)
  • Author(s): Takaichi Okano, jun Saegusa, Keisuke Nishimura, Yo Ueda, Sho Sendo, Soshi Takahashi, Miwa Nishida, Kengo Akashi, Akira Onishi, Akio Morinobu
  • Organizer: 第61回日本リウマチ学会総会・学術集会
• [Presentation] THE CLINICAL FEATURES OF 223 BEHCET'S DISEASE PATIENTS IN JAPAN (2017)
  • Author(s): R. Saito, K. Nishimura, H. Mukoyama, Y. Nakamura, T. Nagamoto, K. Akashi, A. Onishi, Y. Kogata, J. Saegusa, A. Morinobu, T. Yokota
  • Organizer: EULAR Congress 2017 Annual European Congress of Rheumatology
  • Int'l Joint Research
• [Presentation] Dual Effect of 3-Bromopyruvate on Both Th17 and Treg Cell Differentiation and Dendritic Cell Activation Ameliorates Autoimmune Arthritis in Mice (2016)
  • Author(s): OKANO Takaichi, SAEGUSA Jun, NISHIMURA Keisuke, UEDA Yo, SENDO Sho, TAKAHASHI Soshi, MORINOBU Akio
  • Organizer: 第45回日本免疫学会総会・学術集会
  • Place of Presentation: 沖縄コンベンションセンター、ラグナガーデンホテル(沖縄県宜野湾市)
  • Year and Date: 2016-12-05
• [Presentation] KNOCKOUT OF ENDOTHELIN TYPE B RECEPTOR SIGNALING ATTENUATES BLEOMYCIN-INDUCED SKIN SCLEROSIS IN MICE (2016)
  • Author(s): K. Akashi, J. Saegusa, S. Sendo, K. Nishimura, K. Tsuda, I. Naka, T. Okano, S. Takahashi, M. Nishida, Y. Ueda, A. Morinobu
  • Organizer: EULAR Congress 2016 Annual European Congress of Rheumatology
  • Place of Presentation: ロンドン（イギリス）
  • Year and Date: 2016-06-08
  • Int'l Joint Research
• [Presentation] 3-BROMOPYRUVATE AMELIORATES AUTOIMMUNE ARTHRITIS BY EXERTING A DUAL EFFECT ON BOTH TH17 AND TREG CELL DIFFERENTIATION AND DENDRITIC CELL ACTIVATION (2016)
  • Author(s): T. Okano, J. Saegusa, K. Nishimura, S. Takahashi, S. Sendo, Y. Ueda, A. Onishi, A. Morinobu.
  • Organizer: EULAR Congress 2016 Annual European Congress of Rheumatology
  • Place of Presentation: ロンドン（イギリス）
  • Year and Date: 2016-06-08
  • Int'l Joint Research
• [Presentation] SKGマウス肺病変の進展に伴って増加するCD11b+Gr1dim cellはGM-CSFによって誘導される (2016)
  • Author(s): 千藤 荘, 仲 郁子, 津田 耕作, 岡野 隆一, 西田 美和, 明石 健吾, 高橋 宗史, 上田 洋, 西村 啓佑, 大西 輝, 古形 芳則, 三枝 淳, 森信 暁雄
  • Organizer: 第60回日本リウマチ学会・学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-04-21
• [Presentation] Glutaminase1 inhibitor inhibits synoviocytes proliferation and ameliorates inflammatory arthritis in mice (2016)
  • Author(s): Soshi Takahashi, Jun Saegusa, Ikuko Naka, Kosaku Tsuda, Takaichi Okano, Kengo Akashi, Miwa Nishida, Keisuke Nishimura, Sho Sendo, Yo Ueda, Akira Onishi, Yoshinori Kogata, Akio Morinobu*
  • Organizer: 第60回日本リウマチ学会・学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-04-21