Analysis of CD8+CD26-positive/negative T cell subsets for the development of an innovative therapy and elucidating the pathophysiology of refractory autoimmune diseases

• Project/Area Number: 26860760
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Collagenous pathology/Allergology
• Research Institution: Juntendo University
• Principal Investigator: Hatano Ryo 順天堂大学, 医学(系)研究科(研究院), 特任研究員 (30638789)
• Research Collaborator: ISHII Tomonori ; SEKIGAWA Iwao
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: CD26/DPPIV / T細胞 / SLE / 自己免疫疾患 / 細胞傷害性T細胞 / 共刺激分子 / ヒト免疫 / 共刺激 / 細胞傷害活性 / IL-10 / CD26

Outline of Final Research Achievements

CD26 is a T cell costimulatory molecule, and CD26+ T cells have been suggested to be involved in the pathophysiology of diverse autoimmune diseases. Since the role of CD26 in the pathophysiology of SLE still remains to be elucidated, our objective is to characterize the CD26-positive or negative T cell subsets in SLE patients. Human CD4+ or CD8+ T cells were purified from PBMCs of SLE patients or healthy adult volunteers, and we examined the phenotypes of CD26-positive or negative subsets. In addition to CD8+CD26nega T cells, CD4+CD26nega T cells were also markedly increased in SLE patients, and these cells exhibited CD28negaCD57+PerforinhiGranzyme Bhi cytotoxic potential. It takes more than 24 months for the patients with a large number of these subsets to reduce the daily dose of prednisolone to less than 10 mg after the initial treatment, strongly suggesting that CD26nega cytotoxic T cells are involved in the pathophysiology of steroid-resistant SLE.

Research Products

• [Journal Article] Establishment of intestinal epithelial cell line derived from fetal mouse colon and its immune-related characteristics - Comparison with mouse small intestinal epithelial cell line -. (2018)
  • Author(s): Iwamoto T, Totsuka M, Yamada K, Emoto T, Hatano R, Shimizu M.
  • Journal Title: Cytotechnology Volume: in press
  • Peer Reviewed
• [Journal Article] A novel role for CD26/dipeptidyl peptidase IV as a therapeutic target in selected immune disorders and cancers. (2018)
  • Author(s): Ohnuma K, Hatano R, Komiya E, Otsuka H, Itoh T, Iwao N, Kaneko Y, Yamada T, Dang NH, Morimoto C.
  • Journal Title: Front Biosci Volume: in press
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A possible role for CD26/DPPIV enzyme activity in the regulation of psoriatic pruritus. (2017)
  • Author(s): Komiya, E. Hatano, R. Otsuka, H. Itoh, T. Yamazaki, H. Yamada, T. Dang, N. H. Tominaga, M. Suga, Y. Kimura, U. Takamori, K. Morimoto, C. Ohnuma, K.
  • Journal Title: J Dermatol Sci. Volume: 印刷中 Pages: 212-221
  • DOI: 10.1016/j.jdermsci.2017.03.005
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Role of IL-26+CD26+CD4 T cells in pulmonary chronic graft-versus-host disease and treatment with caveolin-1-Ig Fc conjugate. (2016)
  • Author(s): Ohnuma, K. Hatano, R. Itoh, T. Iwao, N. Dang, N. H. Morimoto, C.
  • Journal Title: Crit Rev Immunol. Volume: 36 Pages: 239-267
  • DOI: 10.1615/critrevimmunol.2016018772
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Establishment of anti-mesothelioma monoclonal antibodies. (2016)
  • Author(s): Mizutani N, Abe M, Matsuoka S, Kajino K, Wakiya M, Ohtsuji N, Hatano R, Morimoto C, Hino O
  • Journal Title: BMC Res Notes. Volume: 9 Pages: 324-324
  • DOI: 10.1186/s13104-016-2128-x
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of VEGF-dependent angiogenesis by the anti-CD82 monoclonal antibody 4F9 through regulation of lipid raft microdomains. (2016)
  • Author(s): Nomura, S. Iwata, S. Hatano, R. Komiya, E. Dang, N. H. Iwao, N. Ohnuma, K. Morimoto, C.
  • Journal Title: Biochem Biophys Res Commun. Volume: 474 Pages: 111-117
  • DOI: 10.1016/j.bbrc.2016.04.081
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] DPP4 in anti-tumor immunity: going beyond the enzyme (2015)
  • Author(s): Ohnuma K, Hatano R, Morimoto C.
  • Journal Title: Nat Immunol Volume: 16 Pages: 791-2
  • DOI: 10.1038/ni.3210
  • Peer Reviewed / Open Access
• [Journal Article] The role of Cas-L/NEDD9 as a regulator of collagen-induced arthritis in a murine model (2015)
  • Author(s): Tomoki Katayose, Satoshi Iwata, Naoki Oyaizu, Osamu Hosono, Taketo Yamada, Nam H Dang, Ryo Hatano, Hirotoshi Tanaka, Kei Ohnuma, Chikao Morimoto
  • Journal Title: Biochem Biophys Res Commun. Volume: 印刷中 Pages: 1069-1075
  • DOI: 10.1016/j.bbrc.2015.03.156
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Modulation of immunological responses and amelioration of collagen-induced arthritis by the novel roxithromycin derivative 5-I (2015)
  • Author(s): Otsuki N, Iwata S, Yamada T, Hosono O, Dang NH, Hatano R, Ohnuma K, Morimoto C.
  • Journal Title: Mod Rheumatol Volume: 25 Pages: 562-570
  • DOI: 10.3109/14397595.2014.983262
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Regulation of pulmonary graft-versus-host disease by IL-26+CD26+CD4 T lymphocytes. (2015)
  • Author(s): Ohnuma K, Hatano R, Aune TM, Otsuka H, Iwata S, Dang NH, Yamada T, Morimoto C.
  • Journal Title: J Immunol. Volume: 194(8) Pages: 3697-3712
  • DOI: 10.4049/jimmunol.1402785
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] CD26-mediated induction of EGR2 and IL-10 as potential 4 regulatory mechanism for CD26 costimulatory pathway (2015)
  • Author(s): Hatano R, Ohnuma K, Otsuka H, Komiya E, Taki I, Iwata S, Dang NH, Okumura K, Morimoto C.
  • Journal Title: Journal of Immunology Volume: Vol 194 Pages: 960-72
  • DOI: 10.4049/jimmunol.1402143
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Comparison of two commercial ELISAs against an in-house ELISA for measuring soluble CD26 in human serum (2015)
  • Author(s): Ohnuma K, Saito T, Hatano R, Hosono O, Iwata S, Dang NH, Ninomiya H, Morimoto C.
  • Journal Title: J Clin Lab Anal Volume: Vol 29 Pages: 106-11
  • DOI: 10.1002/jcla.21736
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] CD26-mediated regulation of periostin expression contributes to migration and invasion of malignant pleural mesothelioma cells. (2014)
  • Author(s): Komiya E, Ohnuma K, Yamazaki H, Hatano R, Iwata S, Okamoto T, Dang NH, Yamada T, Morimoto C.
  • Journal Title: Biochem. Biophys. Res. Commun Volume: Vol 447 Pages: 609-15
  • DOI: 10.1016/j.bbrc.2014.04.037
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Regulation of somatostatin receptor 4-mediated cytostatic effects by CD26 in malignant pleural mesothelioma (2014)
  • Author(s): Yamamoto J, Ohnuma K, Hatano R, Okamoto T, Komiya E, Yamazaki H, Iwata S, Dang NH, Aoe K, Kishimoto T, Yamada T, Morimoto C.
  • Journal Title: Br J Cancer Volume: Vol 110 Pages: 2232-2245
  • DOI: 10.1038/bjc.2014.151
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Grassypeptolides as Natural Inhibitors of Dipeptidyl Peptidase 8 and T-Cell Activation (2014)
  • Author(s): Kwan JC, Liu Y, Ratnayake R, Hatano R, Kuribara A, Morimoto C, Ohnuma K, Paul VJ, Ye T, Luesch H.
  • Journal Title: Chembiochem Volume: Vol 15 Pages: 799-804
  • DOI: 10.1002/cbic.201300762
  • Peer Reviewed / Open Access
• [Presentation] 急性GVHDマウスモデルにおけるHMGB1の動態に関する検討. (2018)
  • Author(s): 岩尾憲明、大沼圭、大塚春奈、波多野良、古宮栄利子、伊藤匠、森本幾夫.
  • Organizer: 第40回日本造血細胞移植学会、札幌市教育文化会館(北海道札幌市)
• [Presentation] CD26/DPPIV regulates mechanical itch in a mechanistically distinct manner from chemical itch. (2017)
  • Author(s): Eriko Komiya, Ryo Hatano, Haruna Otsuka, Takumi Itoh, Hiroto Yamazaki, Mitsutoshi Tominaga, Kenji Takamori, Kei Ohnuma, Chikao Morimoto.
  • Organizer: 第42回日本研究皮膚科学会、高知市文化プラザかるぽーと(高知県高知市)
• [Presentation] IL-26 facilitates angiogenesis and skin inflammation via inducing FGF2 production in a murine model of imiquimod-induced psoriasis. (2017)
  • Author(s): Takumi Itoh, Ryo Hatano, Haruna Otsuka, Noriaki Iwao, Satoshi Iwata, Taketo Yamada, Chikao Morimoto.
  • Organizer: 第46回日本免疫学会、仙台国際センター(宮城県仙台市)
• [Presentation] The regulation of pruritus in psoriasis and atopic dermatitis -a possible role for CD26/DPPIV. (2017)
  • Author(s): Eriko Komiya, Ryo Hatano, Haruna Otsuka, Takumi Itoh, Hiroto Yamazaki, Taketo Yamada, Yasushi Suga, Utako Kimura, Mitsutoshi Tominaga, Kenji Takamori, Kei Ohnuma, Chikao Morimoto.
  • Organizer: 9th World Congress on Itch, Novotel Centrum, Wroclaw, Poland
  • Int'l Joint Research
• [Presentation] 全身性エリテマトーデスのステロイド治療抵抗性とCD26陰性T細胞サブセットとの関係性について. (2017)
  • Author(s): 波多野良、大沼圭、石井智徳、岩田哲史、奥村康、関川巖、森本幾夫.
  • Organizer: 第61回日本リウマチ学会、福岡国際会議場(福岡県福岡市)
• [Presentation] CD26/DPPIV-mediated regulation of pruritus in psoriasis. (2016)
  • Author(s): Eriko Komiya, Ryo Hatano, Haruna Otsuka, Takumi Itoh, Taketo Yamada, Mitsutoshi Tominag, Kenji Takamori, Kei Ohnuma, Chikao Morimoto.
  • Organizer: 第41回研究皮膚科学会
  • Place of Presentation: 仙台国際センター(宮城県仙台市)
  • Year and Date: 2016-11-09
• [Presentation] 乾癬においてCD26/DPPIVはsubstance Pの切断を促進してかゆみを調節する. (2016)
  • Author(s): 古宮栄利子, 波多野良, 大塚春奈, 伊藤匠, 山田健人, 冨永光俊, 高森建二, 大沼圭, 森本幾夫.
  • Organizer: 第31回日本乾癬学会
  • Place of Presentation: ホテル東日本宇都宮(栃木県宇都宮市)
  • Year and Date: 2016-09-02
• [Presentation] CD26陽性T細胞サブセットに基づく全身性エリテマトーデスの病態解析. (2016)
  • Author(s): 波多野良, 大沼圭, 石井智徳, 岩田哲史, 奥村康, 関川巖, 森本幾夫.
  • Organizer: 第60回日本リウマチ学会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
  • Year and Date: 2016-04-21
• [Presentation] Anti-interleukin-26 therapy for lung fibrosis of GVHD. (2015)
  • Author(s): Ryo Hatano, Taketo Yamada, Haruna Otsuka, Eriko Komiya, Noriaki Iwao, Ko Okumura, Chikao Morimoto, Kei Ohnuma.
  • Organizer: 第77回日本血液学会.
  • Place of Presentation: ホテル日航金沢(石川県金沢市)
  • Year and Date: 2015-10-16
• [Presentation] T細胞共刺激分子CD26に基づく全身性エリテマトーデスの病態および疾患活動性の新規バイオマーカーの探索. (2015)
  • Author(s): 波多野良, 大沼圭, 岩田哲史, 石井智徳, 関川巖, 森本幾夫.
  • Organizer: 第59回日本リウマチ学会.
  • Place of Presentation: 名古屋国際会議場(愛知県名古屋市)
  • Year and Date: 2015-04-23
• [Presentation] IL-10産生誘導によるCD26共刺激経路のnegative feedback機構の解析. (2014)
  • Author(s): 波多野良, 大沼圭, 岩田哲史, 石井智徳, 関川巖, 森本幾夫.
  • Organizer: 第58回日本リウマチ学会.
  • Place of Presentation: グランドプリンスホテル新高輪 (東京都港区)
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] DPP4阻害薬の服用によって誘発される多関節症とそのバイオマーカー. (2014)
  • Author(s): 大沼圭, 斎藤辰彦, 波多野良, 岩田哲史, 鈴木博史, 森本幾夫.
  • Organizer: 第58回日本リウマチ学会.
  • Place of Presentation: グランドプリンスホテル新高輪 (東京都港区)
  • Year and Date: 2014-04-24 – 2014-04-26
• [Book] Advances in Medicine and Biology (2018)
  • Author(s): Hatano R, Ohnuma K, Yamada T, Okamoto T, Komiya E, Otsuka H, Itoh T, Yamazaki H, Iwao N, Kaneko Y, Dang NH, Morimoto C.
  • Total Pages: 44
  • Publisher: Nova Science Publishers, Inc., Hauppauge, NY
• [Book] Horizons in Cancer Research. (2017)
  • Author(s): Ohnuma K, Hatano R, Yamazaki H, Kaneko Y, Dang NH, Morimoto C.
  • Total Pages: 34
  • Publisher: Nova Science Publishers, Inc.
• [Patent(Industrial Property Rights)] 抗ヒトCD26モノクローナル抗体. (2018)
  • Inventor(s): 森本幾夫、波多野良、山田健人、大沼圭.
  • Industrial Property Rights Holder: 学校法人順天堂、学校法人埼玉医科大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-049308
  • Filing Date: 2018
  • Application Year: 2018
• [Patent(Industrial Property Rights)] 抗ヒトIL-26抗体. (2017)
  • Inventor(s): 森本幾夫、波多野良、大沼圭、伊藤匠.
  • Industrial Property Rights Holder: 学校法人順天堂
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-231439
  • Filing Date: 2017
  • Application Year: 2017
• [Patent(Industrial Property Rights)] 抗CD10抗体. (2017)
  • Inventor(s): 水谷奈津子、阿部雅明、松岡周二、樋野興夫、大辻奈穂美、波多野良.
  • Industrial Property Rights Holder: 学校法人順天堂、日本抗体医薬株式会社
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017
  • Application Year: 2017
• [Patent(Industrial Property Rights)] 免疫抑制剤. (2014)
  • Inventor(s): 森本幾夫, 大沼圭, 波多野良.
  • Industrial Property Rights Holder: 順天堂大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-199260
  • Filing Date: 2014-09-29
  • Application Year: 2014