Basic research of defining the function of CD26 on human immune system and its clinical application for autoimmune diseases.

• Project/Area Number: 22390200
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Juntendo University (2012); The University of Tokyo (2010-2011)
• Principal Investigator: MORIMOTO Chikao 順天堂大学, 大学院・医学研究科, 客員教授 (30119028)
• Co-Investigator(Kenkyū-buntansha): IWATA Satoshi 東京大学, 医科学研究所, 特任講師 (00396871) ; HOSONO Osamu 東京大学, 医科学研究所, 講師 (50190210)
• Co-Investigator(Renkei-kenkyūsha): YAMADA Taketo 慶應義塾大学, 医学部, 准教授 (60230463)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2012: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2011: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2010: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
• Keywords: CD26 / DPPIV 酵素 / CD28 / CD8T 細胞 / グランザイム B / xeno-GVHD / ヒト化 CD26 抗体 / IL-10 / CD26分子 / 共刺激 / 自己免疫疾患 / ヒト免疫系 / CD8T細胞 / GVHD / CD28分子 / サイトカイン産生 / グランザイムB / 細胞障害作用 / CD26/DPPIV / ヒト化CD26抗体 / Granzyme B / 糖尿病 / Fas Ligand

Research Abstract

CD26 is a 110-KDa surface glycoprotein with DPPIV enzyme activity that has many biological functions. We showed that CD26 costimulation induced IL -10 production and CTLA-4 expression in CD4 T cells compared to CD28 costimulation suggesting that CD26 coslimulation has a negative activation pathway. We also showed that CD26 (high) CD8 T cells belong to the early effector memory T-cell subset and that CD26 mediated co-stimulation of CD8+T cells exerts a cytotoxic effect preferentially via gramzyme B, TNF-α and Fas-ligand compared to that obtained through CD28-mediated costimulation. Moreover, we showed that CD26+T cells play an important role in GVHD mediated by human lymphocytes, and that anti-CD26mAb is an effective treatment for GVHD in hu-PBL-NOG mouse model. In addition we found that genetical or pharmacological inhibition of CD26/DPPIV enhances endothelial growth both in vitro and in vivo, suggesting that DPPIV inhibition plays a pivotal role in endothelial growth and may have a potential role in the recovery of local circulation following diabetic vascular complications. Our results strongly suggest that CD26/DPPIV is an appropriate therapeutic target for the treatment of selected immune disorders.

Research Products

• [Journal Article] Characterization of cancer stem cell properties of CD24 and CD26-positive human malignant mesothelioma cells (2014)
  • Author(s): Yamazaki H, Naito M, Ghani F, Dang NH, Iwata S, Morimoto C
  • Journal Title: Biochem Biophys Res Commun Volume: 419 Pages: 529-36
  • DOI: 10.1016/j.bbrc.2012.02.054
  • Peer Reviewed
• [Journal Article] CD26-mediated costimulation in human CD8+T cells provokes effector function via proinflammatory cytokine production. (2013)
  • Author(s): Hatano R, Ohnuma K, Yamamoto J, Dang NH, Morimoto C
  • Journal Title: Immunol. Volume: 138 Pages: 165-172
  • DOI: 10.1111/imm.12028
  • Peer Reviewed
• [Journal Article] Multiple effects of repetitive transcranial magnetic stimulation on neuropsychiatric disorders (2013)
  • Author(s): Ikeda T, Morimoto C, et al.
  • Journal Title: Biochem Biophys Res Commun Volume: in press Pages: 121-7
  • DOI: 10.1016/j.bbrc.2013.03.017
  • Peer Reviewed
• [Journal Article] CD9 expression as a favorable prognostic marker for patients with malignant mesothelioma (2013)
  • Author(s): Amatya VJ, Morimoto C, et al.
  • Journal Title: Oncol Rep Volume: 29 Pages: 21-28
  • DOI: 10.3892/or.2012.2116
  • Peer Reviewed
• [Journal Article] Cardiomyocyte-specific overexpression of HEXIM1 prevents right ventricular hypertrophy in hypoxia-induced pulmonary hypertension in mice (2013)
  • Author(s): Yoshikawa N, Morimoto C, et al.
  • Journal Title: PLoS One Volume: 7
  • DOI: 10.1371/journal.pone.0052522
  • Peer Reviewed
• [Journal Article] CD26 overexpression is associated with prolonged survival and enhanced chemosensitivity in malignant pleural mesothelioma. (2012)
  • Author(s): Aoe K, Amatya VJ, Fujimoto N, Ohnuma K, Hosono O, Hiraki A, Fujii M, Yamada T, Dang NH, Takeshima Y, Inai K, Kishimoto T, Morimoto C
  • Journal Title: Clin Cancer Res. Volume: 18(5) Pages: 1447-1456
  • DOI: 10.1158/1078-0432.ccr-11-1990
  • Peer Reviewed
• [Journal Article] Impact of the Integrin Signaling Adaptor Protein NEDD9 on Prognosis and Metastatic Behavior of Human Lung Cancer (2012)
  • Author(s): Kondo S, Morimoto C, et al.
  • Journal Title: Clin Cancer Res Volume: 18 Pages: 6326-38
  • DOI: 10.1158/1078-0432.ccr-11-2162
  • Peer Reviewed
• [Journal Article] Overexpression of CD26/DPPIV in mesothelioma tissue and mesothelioma cell lines (2011)
  • Author(s): Amatya VJ, Takeshima Y, Kushitani K, Yamada T, Morimoto C, Inai K
  • Journal Title: Oncol Rep Volume: 26 Pages: 1369-1375
  • DOI: 10.3892/or.2011.1449
  • NAID: 120005300470
• [Journal Article] Crosstalk between glucocorticoid receptor and nutritional sensor mTOR in skeletal muscle (2011)
  • Author(s): S himizu N, Yoshikawa N, Ito N, Maruyama T, Suzuki Y, Takeda S, Nakae J, Tagata Y, Nishitani S, Takehana K, Sano M, Fukuda K, Suematsu M, Morimoto C, Tanaka H
  • Journal Title: Cell Metabolism Volume: 13 Pages: 170-182
  • DOI: 10.1016/j.cmet.2011.01.001
  • Peer Reviewed
• [Journal Article] Mechanisms of confluence-dependent expression of CD26 in colon cancer cell lines (2011)
  • Author(s): Abe M, Havre PA, Urasaki Y, Ohnuma K, Morimoto C, Dang LH, Dang NH
  • Journal Title: BMC Cancer Volume: 11 Pages: 51-51
  • DOI: 10.1186/1471-2407-11-51
  • Peer Reviewed
• [Journal Article] Diet-Induced Adipose Tissue Inflammation and Liver Steatosis Are Prevented by DPP-4 Inhibition in Diabetic Mice. (2011)
  • Author(s): Shirakawa J, Fujii H, Ohnuma K, Sato K, Ito Y, Kaji M, Sakamoto E, Koganei M, Sasaki H, Nagashima Y, Amo K, Aoki K, Morimoto C, Takeda E, Terauchi Y
  • Journal Title: Diabetes. Volume: 60(4) Pages: 1246-1257
  • DOI: 10.2337/db10-1338
  • Peer Reviewed
• [Journal Article] Regulation of cancer stem cell properties by CD9 in human B-acute lymphoblastic leukemia (2011)
  • Author(s): Yamazaki H, Inukai T, et al
  • Journal Title: Biochem Biophys Res Commun Volume: 409 Pages: 14-21
  • DOI: 10.1016/j.bbrc.2011.04.098
  • Peer Reviewed
• [Journal Article] Identification of cancer stem cell markers in human malignant mesothelioma cells. (2011)
  • Author(s): Ghani FI, Yamazaki H, Iwata S, Okamoto T, Aoe K, Okabe K, Mimura Y, Fujimoto N, Kishimoto T, Yamada T, Xu CW, Morimoto C.
  • Journal Title: Biochem Biophys Res Commun. Volume: 404 Pages: 735-742
  • Peer Reviewed
• [Journal Article] Mechanisms of confluence-dependent expression of CD26 in colon cancer cell lines. (2011)
  • Author(s): Abe M, Havre PA, Urasaki Y, Ohnuma K, Morimoto C, Dang LH, Dang NH.
  • Journal Title: BMC Cancer. Volume: 11 Pages: 51-84
  • Peer Reviewed
• [Journal Article] Dipeptidyl peptidase in autoimmune pathophysiology (2011)
  • Author(s): Ohnuma K, Hosono O, Dang NH, Morimoto C.
  • Journal Title: Adv Clin Chem. Volume: 53 Pages: 51-51
  • Peer Reviewed
• [Journal Article] Diet-Induced Adipose Tissue Inflammation and Liver Steatosis Are Prevented by DPP-4 Inhibition in Diabetic Mice. (2011)
  • Author(s): Shirakawa J, Fujii H, Ohnuma K, Sato K, Ito Y, Kaji M, Sakamoto E, Koganei M, Sasaki H, Nagashima Y, Amo K, Aoki K, Morimoto C, Takeda E, Terauchi Y.
  • Journal Title: Diabetes. Volume: 60 Pages: 1246-1257
  • Peer Reviewed
• [Journal Article] Crosstalk between glucocorticoid receptor and nutritional sensor mTOR in skeletal muscle. (2011)
  • Author(s): Shimizu N, Yoshikawa N, Ito N, Maruyama T, Suzuki Y, Takeda S, Nakae J, Tagata Y, Nishitani S, Takehana K, Sano M, Fukuda K, Suematsu M, Morimoto C, Tanaka H.
  • Journal Title: Cell Metab. Volume: 13 Pages: 170-182
  • Peer Reviewed
• [Journal Article] Targeted therapy by monoclonal antibodies. (2011)
  • Author(s): Ohnuma K, Morimoto C.
  • Journal Title: Nippon Rinsho. Volume: 68 Pages: 1841-1847
  • NAID: 40017319588
  • Peer Reviewed
• [Journal Article] Targeted therapy by monoclonal antibodies (2010)
  • Author(s): Ohnuma K, Morimoto C
  • Journal Title: Nippon Rinsho Volume: 68 Pages: 1841-7
  • NAID: 40017319588
• [Journal Article] Inhibition of dipeptidyl peptidase 4 regulates microvascular endothelial growth induced by inflammatory cytokines (2010)
  • Author(s): Takasawa W, Ohnuma K, Hatano R, Endo Y, Dang NH, Morimoto C
  • Journal Title: Biochem Biophys Res Commun Volume: 40 Pages: 7-12
  • DOI: 10.1016/j.bbrc.2010.08.112
  • Peer Reviewed
• [Journal Article] Aqueous extract of Carica papaya leaves exhibits anti-tumor activity and immunomodulatory effects. (2010)
  • Author(s): Otsuki N, Dang NH, Kumagai E, Kondo A, Iwata S, Morimoto C.
  • Journal Title: J Ethnopharmacol. Volume: 127 Pages: 760-767
  • Peer Reviewed
• [Journal Article] Optimal stimulation for CD70 induction on human monocyte-derived dendritic cells and the importance of CD70 in naive CD4(+) T-cell differentiation. (2010)
  • Author(s): Arimoto-Miyamoto K, Kadowaki N, Kitawaki T, Iwata S, Morimoto C, Uchiyama T.
  • Journal Title: Immunology Volume: 130 Pages: 137-149
  • Peer Reviewed
• [Journal Article] Inhibition of dipeptidyl peptidase 4 regulates microvascular endothelial growth induced by inflammatory cytokines. (2010)
  • Author(s): Takasawa W, Ohnuma K, Hatano R, Endo Y, Dang NH, Morimoto C.
  • Journal Title: Biochem Biophys Res Commun Volume: 401 Pages: 7-12
  • Peer Reviewed
• [Presentation] First‐in‐Human Phase I administration of YS110, a humanized monoclonal antibody directed against the CD26 molecule in cancer patients. (2012)
  • Author(s): Angevin E, Morimoto C, et al.
  • Organizer: 37th The European Society for Medical Oncology (ESMO) Congress
  • Place of Presentation: Vienna, Austria
• [Presentation] CD26 overexpression is associated with prolonged survival and enhanced chemosensitivity in malignant pleural mesothelioma. (2012)
  • Author(s): Aoe K, Morimoto C, et al.
  • Organizer: 11th International Conference of the International Mesothlioma Interest Group
  • Place of Presentation: Boston, USA
• [Presentation] Humanized anti-CD26 mAb Leads to Prophylaxis and Treatment of GVHD in Hu-PBL-NOG Model Mice. (2012)
  • Author(s): Hatano R, Morimoto C, et al.
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都, 日本
• [Presentation] The Current Status of Drug Development and the Role of Clinical Trial Centers in Japan (2011)
  • Author(s): Chikao Morimoto
  • Organizer: International Symposium for Clinical Trial
  • Place of Presentation: Jeju, Korea(招待講演)
  • Year and Date: 2011-10-07
• [Book] Dipeptidyl peptidase in autoimmune pathophysiology (2011)
  • Author(s): Ohnuma K, Hosono O, Dang NH, Morimoto C
  • Publisher: Adv Clin Chem
• [Book] Advances in Clinical Chemistory (2011)
  • Author(s): Ohnuma K, Hosono O, Dang NH, Morimoto C
  • Publisher: Dipeptidyl peptidase in autoimmune pathophysiology
• [Book] Stem cell property for T-cell malignancy. T-Cell Malignancies: Recent Developments and Novel Therapeutic Approaches (2010)
  • Author(s): Yamazaki H and Morimoto C
  • Publisher: Edited by Dang NH
• [Book] The role of CD26 in T-cell biology and T-cell malignancies. T-Cell Malignancies: Recent Developments and Novel Therapeutic Approaches (2010)
  • Author(s): Havre PA, Dang LH, Abe M, Urasaki Y, Ohnuma K, Morimoto C, Dang NH
  • Publisher: Edited by Dang NH
• [Book] The role of CD26 in T-cell biology and T-cell malignancies. T-Cell Malignancies : Recent Developments and Novel Therapeutic Approaches. (2010)
  • Author(s): Havre PA, Dang LH, Abe M, Urasaki Y, Ohnuma K, Morimoto C, Dang NH.
  • Publisher: Research Signpost
• [Book] T-Cell Malignancies : Recent Developments and Novel Therapeutic Approaches. (2010)
  • Author(s): Yamazaki H, Morimoto C.
  • Publisher: Research Signpost
• [Remarks] 免疫病態分野ホームページ
  • URL: http://www.ims.u-tokyo.ac.ip/cimmuno/