Mechanism of lung fibrosis in chronic GVHD

• Project/Area Number: 15H04879
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Juntendo University
• Principal Investigator: OHNUMA Kei 順天堂大学, 医学(系)研究科(研究院), 准教授 (10396872)
• Co-Investigator(Kenkyū-buntansha): 森本 幾夫 順天堂大学, 医学(系)研究科(研究院), 特任教授 (30119028) ; 岩尾 憲明 順天堂大学, 医学部, 准教授 (00309139) ; 岩田 哲史 順天堂大学, 医学(系)研究科(研究院), 非常勤講師 (00396871)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2017: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2016: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2015: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 慢性GVHD / CD26 / Caveolin-1 / IL-26 / 造血幹細胞移植 / GVHD / caveolin-1 / 線維化 / DPP4 / 移植免疫学 / 小児血液学

Outline of Final Research Achievements

Obliterative bronchiolitis (OB) is the only manifestation of pulmonary chronic GVHD (cGVHD). We identified a novel effect of IL-26 on cGVHD. Humanized cGVHD mice exhibited OB with increased collagen deposition and predominant infiltration with human IL-26CD26CD4T cells. IL-26 increased collagen synthesis in fibroblasts and that collagen contents were increased in a murine GVHD model using IL26 Tg mice. IA significant increase in IL-26 production by CD4T cells following CD26 costimulation, while immunoglobulin Fc domain fused with the N-terminal of caveolin-1, the ligand for CD26, (Cav-Ig) effectively inhibited production of IL-26. Administration of Cav-Ig before or after onset of GVHD impeded the development of cGVHD without interrupting engraftment of donor-derived human cells, with preservation of the GVL effect. We concluded that cGVHD of the lungs is caused in part by IL-26CD26CD4T cells, and that treatment with Cav-Ig could be beneficial for cGVHD prevention and therapy.

Research Products

• [Int'l Joint Research] University of Florida/National Institute on Aging(米国)
• [Int'l Joint Research] フロリダ大学/ヴァンダービルト大学(米国)
• [Int'l Joint Research] フロリダ大学/ヴァンダービルト大学(米国)
• [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 Issue: 3 Pages: 212-221
  • DOI: 10.1016/j.jdermsci.2017.03.005
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] First-in-human phase 1 of YS110, a monoclonal antibody directed against CD26 in advanced CD26-expressing cancers (2017)
  • Author(s): Angevin, E. Isambert, N. Trillet-Lenoir, V. You, B. Alexandre, J. Zalcman, G. Vielh, P. Farace, F. Valleix, F. Podoll, T. Kuramochi, Y. Miyashita, I. Hosono, O. Dang, N. H. Ohnuma, K. Yamada, T. Kaneko, Y. Morimoto, C.
  • Journal Title: Br J Cancer Volume: 印刷中 Issue: 9 Pages: 1-9
  • DOI: 10.1038/bjc.2017.62
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of senescent cell surface targetable protein DDP4. (2017)
  • Author(s): 71.Kim KM, Noh JH, Bodogai M, Martindale JL, Yang X, Indig FE, Basu SK, Ohnuma K, Morimoto C, Johnson PF, Biragyn A, Abdelmohsen K, Gorospe M.
  • Journal Title: Genes Dev Volume: 31 Issue: 15 Pages: 1529-1534
  • DOI: 10.1101/gad.302570.117
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Focus on CD26/Dipeptidyl Peptidase IV as a Therapeutic Target. (2017)
  • Author(s): Doonan BP, Ohnuma K, Dang LH, Morimoto C, Dang NH.
  • Journal Title: Current Cancer Therapy Reviews Volume: 13 Issue: 2 Pages: 1-13
  • DOI: 10.2174/1573394713666170907160734
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Development of New Therapy for Malignant Mesothelioma Based on CD26 Molecule (2016)
  • Author(s): Morimoto, C. Ohnuma, K.
  • Journal Title: Gan To Kagaku Ryoho Volume: 43 Pages: 855-62
• [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 Issue: 1 Pages: 111-7
  • DOI: 10.1016/j.bbrc.2016.04.081
  • 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 Issue: 3 Pages: 239-267
  • DOI: 10.1615/critrevimmunol.2016018772
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Remission of remitting seronegative symmetrical synovitis with pitting edema after unrelated cord blood transplantation for myelodysplastic syndrome. (2015)
  • Author(s): Ishii H, Konuma T, Ohnuma K, Hosono O, Tanaka H, Kato S, Tojo A, Takahashi S.
  • Journal Title: Ann Hematol. Volume: 95 Issue: 3 Pages: 523-524
  • DOI: 10.1007/s00277-015-2555-0
  • Peer Reviewed
• [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 Issue: 8 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 Bilphys Res Commun Volume: 印刷中 Issue: 4 Pages: 1069-75
  • DOI: 10.1016/j.bbrc.2015.03.156
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Deep venous thrombosis was not detected after total knee arthroplasty in Japanese patients with haemophilia. (2015)
  • Author(s): Takedani H, Ohnuma K, Hirose J.
  • Journal Title: Haemophilia Volume: 21 Issue: 5 Pages: 585-588
  • DOI: 10.1111/hae.12643
  • Peer Reviewed
• [Journal Article] CD26-mediated induction of EGR2 and IL-10 as potential 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: J Immunol. Volume: Vol 194 Issue: 3 Pages: 960-72
  • DOI: 10.4049/jimmunol.1402143
  • Peer Reviewed / Open Access
• [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) Issue: 8 Pages: 3697-712
  • DOI: 10.4049/jimmunol.1402785
  • Peer Reviewed / Acknowledgement Compliant
• [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、関川嚴、森本幾夫
  • Organizer: 日本リウマチ学会総会
• [Presentation] 急性GVHDマウスモデルにおけるHMGB1の動態に関する検討 (2017)
  • 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: 日本造血幹細胞移植学会総会
• [Presentation] CD26/DPPIV-mediated regulation of pruritus in psoriasis. (2016)
  • Author(s): Komiya E, Hatano R, Otsuka H, Itoh T, Yamada T, Tomonaga M, Takamori K, Ohnuma K, Morimoto C.
  • Organizer: 第41回研究皮膚科学会 年次学術大会・総会
  • Place of Presentation: 仙台市
  • Year and Date: 2016-12-09
• [Presentation] 乾癬においてCD26/DPPIVはsubstance Pを切断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、高森健二、大沼圭、森本幾夫
  • Organizer: 第31回日本乾癬学会学術大会
  • Place of Presentation: 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総会・学術集会
  • Place of Presentation: 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回日本血液学会学術集会
  • Place of Presentation: 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, 石井智徳, 岩田哲史, 奥村康, 関川巖, 森本幾夫
  • Organizer: 第59回日本リウマチ学会総会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-04-23
• [Book] Horizons in Cancer Research (2017)
  • Author(s): Ohnuma K, Hatano R, Yamazaki H, KanekoY, Dang NH, Morimoto C.
  • Total Pages: 212
  • Publisher: Nova Science Publisher
  • ISBN: 9781536105124
• [Book] Horizons in Cancer Research (2017)
  • Author(s): Ohnuma, K. Hatano, R. Yamazaki, H. Kaneko, Y. Dang, N. H. Morimoto, C.
  • Total Pages: 212
  • Publisher: Nova Science Publishers, Inc.
• [Remarks] 順天堂大学大学院 免疫病・がん先端治療学講座
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/immunity_cancer/
• [Remarks] 順天堂
  • URL: http://www.juntendo.ac.jp/research/collaboration/result/kihukoza.html
• [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