Scientific research of transplantation tolerance targeting CD26/caveolin-1 costimulation pathway

2013 Fiscal Year Final Research Report

• Project/Area Number: 21679005
• Research Category: Grant-in-Aid for Young Scientists (S)
• Allocation Type: Single-year Grants
• Research Field: Pediatrics
• Research Institution: Juntendo University (2012-2013); The University of Tokyo (2009-2011)
• Principal Investigator: OHNUMA Kei 順天堂大学, 医学研究科, 准教授 (10396872)
• Project Period (FY): 2009 – 2013
• Keywords: 移植片対宿主病 / 造血幹細胞移植 / T細胞 / 共刺激 / CD26/DPPIV / Caveolin-1

Research Abstract

In our research, we demonstrated in in vitro experiments that blockade of CD26-mediated T cell costimulation by soluble Fc fusion proteins containing the N-terminal domain of caveolin-1 (Cav-Ig) diminished primary and secondary proliferative responses not only to recall antigen, but also to unrelated allogeneic antigen-presenting cell. To expand the in vitro findings to an in vivo system, we examined CD26-dependent organ injury in a xenogeneic GVHD (xGVHD) murine model. Administration of humanized anti-human CD26 monoclonal antibody (mAb) decreased xGVHD severity and prolonged survival in hu-PBL-NOG mice without loss of engraftment of human T cells, while increasing doses of CTLA4-Ig diminished engraftment of human lymphocytes. Importantly, anti-CD26 mAb treatment preserved the graft-versus-leukemia effects. Altogether, our findings indicate a role for CD26 in the regulation of GVHD and point to CD26 as a novel target for therapeutic intervention in this disease.

Research Products

• [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: 102 Pages: 2232-2245
  • DOI: DOI:10.1038/bjc.2014.151.
  • Peer Reviewed
• [Journal Article] Comparison of Two Commercial ELISAs against an in-house ELISA for measuring soluble CD26 in human serum (2014)
  • 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: (Epub ahead of print)
  • DOI: DOI:10.1002/jcla.21736
  • Peer Reviewed
• [Journal Article] Grassypeptolides as natural inhibitors of dipeptidyl peptidase 8 and T-cell activation (2014)
  • Author(s): Kwan J, Liu Y, Ratnayake R, Hatano R, Kuribara A, Morimoto C, Ohnuma K, Paul VJ, Ye T, Luesch H
  • Journal Title: Chembiochem Volume: 15 Pages: 799-804
  • DOI: DOI: 10.1002/cbic.201300762.
  • Peer Reviewed
• [Journal Article] Establishment of monoclonal anti-human CD26 antibodies suitable for immunostaining of formalin- fixed tissue (2014)
  • Author(s): Hatano R, Yamada T, Matsuoka S, Iwata S, Yamazaki H, Komiya E, Okamoto T, Dang NH, Ohnuma K, Morimoto C
  • Journal Title: Diagn Pathol Volume: 9 Pages: 30
  • DOI: DOI:10.1186/1746-1596-9-30.
  • Peer Reviewed
• [Journal Article] Inhibition of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Infection by Anti-CD26 Monoclonal Antibody (2013)
  • Author(s): Ohnuma K, Haagman BL, Hatano R, Raj VS, Mou H, Iwata S, Dang NH, Bosch BJ, Morimoto C
  • Journal Title: J Virology Volume: 87 Pages: 13892-13899
  • DOI: DOI:10.1128/JVI.02448-13.
  • Peer Reviewed
• [Journal Article] CD9 negatively regulates CD26 expression and inhibits CD26-mediated enhancement of invasive potential of malignant mesothelioma cells (2013)
  • Author(s): Okamoto T, Iwata S, Yamazaki H, Hatano R, Komiya E, Dang NH, Ohnuma K, Morimoto C
  • Journal Title: PLoS One Volume: 9 Pages: e86671
  • DOI: DOI:10.1371/journal.pone.0086671.
  • Peer Reviewed
• [Journal Article] CD26 Expression on T-anaplastic large cell lymphoma (ALCL) line Karpas 299 is associated with increased expression of versican and MT1-MMP and enhanced adhesion (2013)
  • Author(s): Havre P, Ohnuma K, Iwata S, Morimoto C, Dang NH.
  • Journal Title: BMC Cancer Volume: 5 Pages: 517
  • DOI: DOI:10.1186/1471-2407-13-517.
  • Peer Reviewed
• [Journal Article] Polyarthropathy in type 2 diabetes patients treated with DPP4 inhibitors (2013)
  • Author(s): Saito T, Ohnuma K, Dang NH, Hatano R, Ninomiya H, Morimoto C
  • Journal Title: Diabetes Res Clin Pract Volume: 102 Pages: e8-e12
  • DOI: DOI:10.1016/j.diabres.2013.07.010.
  • Peer Reviewed
• [Journal Article] Prevention of acute graft-versus-host disease by humanized anti-CD26 monoclonal antibody (2013)
  • Author(s): Hatano R, Ohnuma K, Yamamoto J, Dang NH, Yamada T, Morimoto C
  • Journal Title: Br J Haematol Volume: 162 Pages: 263-77
  • DOI: DOI:10.1111/bjh.12378.
  • Peer Reviewed
• [Journal Article] Nuclear localization of CD26 induced by a humanized monoclonal antibody inhibits tumor cell growth by modulating of POLR2A transcription (2013)
  • Author(s): Yamada K, Hayashi M, Madokoro H, Nishida H, Du W, Ohnuma K, Sakamoto M, Morimoto C, Yamada T
  • Journal Title: PLoS One Volume: 8 Pages: e62304
  • DOI: DOI:10.1371/journal.pone.0062304.
  • Peer Reviewed
• [Journal Article] CD26-mediated co-stimulation in human CD8^+ T cells provokes effector function via pro-inflammatory cytokine production (2013)
  • Author(s): Hatano R, Ohnuma K, Yamamoto J, Dang NH, Morimoto C
  • Journal Title: Immunology Volume: 138 Pages: 165-172
  • DOI: DOI:10.1111/imm.12028.
  • Peer Reviewed
• [Journal Article] DPP4 (dipeptidyl-peptidase 4) (2013)
  • Author(s): Ohnuma K, Morimoto C
  • Journal Title: Atlas of Genetics and Cytogenetics in Oncology and Hematology Volume: 17 Pages: 301-312
  • DOI: DOI:10.4267/2042/49697.
  • Peer Reviewed
• [Journal Article] Effect of renal impairment on the pharmacokinetics of memantine (2012)
  • Author(s): Ohnuma K et al
  • Journal Title: J Pharmacol Sci Volume: 119 Pages: 324-9
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/22863669.
  • 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: DOI:10.1158/1078-0432.CCR-11-1990.
  • 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
  • DOI: DOI:10.2337/db10-1338.
  • 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
  • DOI: DOI:10.1186/1471-2407-11-51.
  • Peer Reviewed
• [Journal Article] Inhibition of dipeptidyl peptidase 4 regulates micro-vascular 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: DOI:10.1016/j.bbrc.2010.08.112.
  • Peer Reviewed
• [Journal Article] Microscopic polyangiitis initiated with liver dysfunction, calf pain and fever of unknown origin (2010)
  • Author(s): Ohnuma K, Hosono O, Katayose T, Yoshikawa N, Kawasaki H, Fujii T, Oyaizu N, Tanaka H, Morimoto C
  • Journal Title: Rheumatol Int Volume: 30 Pages: 1651-6
  • DOI: DOI:10.1007/s00296-009-1121-2.
  • Peer Reviewed
• [Journal Article] CD26 expression on T cell lines increases SDF-1α-mediated invasion (2009)
  • Author(s): Havre PA, Abe M, Urasaki Y, Ohnuma K, Morimoto C, Dang NH
  • Journal Title: Br J Cancer Volume: 101 Pages: 983-991
  • DOI: DOI:10.1038/sj.bjc.6605236.
  • Peer Reviewed
• [Journal Article] Localization of CD26/DPPIV in nucleus and its nuclear translocation enhanced by anti-CD26 monoclonal antibody with anti-tumor effect (2009)
  • Author(s): Yamada K, Hayashi M, Du W, Ohnuma K, Sakamoto M, Morimoto C, Yamada T
  • Journal Title: Cancer Cell Int Volume: 9 Pages: 17
  • DOI: DOI:10.1186/1475-2867-9-17.
  • Peer Reviewed
• [Journal Article] Histamine H1-receptor anta- gonists with immunomodulating activities : potential use for modulating T helper type 1 (Th1)/Th2 cytokine imbalance and inflammatory responses in allergic diseases (2009)
  • Author(s): Okamoto T, Iwata S, Ohnuma K, Dang NH, Morimoto C
  • Journal Title: Clin Exp Immunol Volume: 157 Pages: 27-34
  • DOI: DOI:10.1111/j.1365-2249.2009.03958.x.
  • Peer Reviewed
• [Journal Article] Blockade of CD26-mediated T cell costimulation with soluble caveolin-1-Ig fusion protein induces anergy in CD4^+ T cells (2009)
  • Author(s): Ohnuma K, Uchiyama M, Hatano R, Takasawa W, Endo Y, Dang NH, Morimoto C
  • Journal Title: Biochem Biophys Res Commun Volume: 386 Pages: 327-332
  • DOI: DOI:10.1016/j.bbrc.2009.06.027.
  • Peer Reviewed
• [Presentation] Humanized anti-CD26 mAb Leads to Prophylaxis and Treatment of GVHD in hu-PBL-NOG Model Mice (2012)
  • Author(s): Hatano R, Ohnuma K, et al
  • Organizer: 第74回日本血液学会総会
  • Place of Presentation: 京都市
  • Year and Date: 2012-10-19
• [Presentation] CD26 blockade by humanized monoclonal antibody leads to prophylaxis and treatment of graft-versus-host disease (GVHD) in hu-PBL NOG model mice (2011)
  • Author(s): Hatano R, Ohnuma K, et al
  • Organizer: The 53th Annual Meeting, American Society of Hematology
  • Place of Presentation: San Diego, LA, USA
  • Year and Date: 20111200
• [Presentation] A novel immunoregulation therapy targeting CD26 molecule for intractable autoimmune diseases : a new aspect of T-cell costimulation blocking therapy (2011)
  • Author(s): Ohnuma K, Morimoto C
  • Organizer: Tokyo- Shanghai Workshop on Rheumatology
  • Place of Presentation: Urayasu, Japan
  • Year and Date: 20111100
• [Presentation] CD26分子を用いたGVHDなど難治性免疫疾患への新規治療法開発 (2011)
  • Author(s): 大沼圭、他
  • Organizer: 第55回日本リウマチ学会総会
  • Place of Presentation: 神戸市
  • Year and Date: 2011-07-17
• [Presentation] A Novel Function of CD26-Mediated Costimulation in the cytotoxic activity of human CD8^+ T cells in xenogeneic graft-versus-host disease mice model (2010)
  • Author(s): Hatano R, Ohnuma K, et al
  • Organizer: The 14th International Congress of Immunolgy
  • Place of Presentation: Kobe, Japan
  • Year and Date: 20100800
• [Presentation] Novel Function of CD26-Mediated Costimulation in the cytotoxic activity of human CD8^+ T cells in xenogeneic chronic GVHD and GVL mice model (2009)
  • Author(s): Hatano R, Ohnuma K, et al
  • Organizer: The 51th Annual Meeting, American Society of Hematology
  • Place of Presentation: New Orleans, LA, USA
  • Year and Date: 20091200
• [Presentation] CD26 expression of vascular endothelium and its role in inflammatory endothelial cell injury (2009)
  • Author(s): 高澤渉、大沼圭、他
  • Organizer: 第71回日本血液学会総会
  • Place of Presentation: 京都市
  • Year and Date: 2009-10-24
• [Book] Dipeptidyl peptidase in autoimmune pathophysiology. In : Makowski GS, eds. Advances in Clinical Chemistry Vol 53 (2011)
  • Author(s): Ohnuma K, Hosono O, Dang NH, Morimoto C
  • Total Pages: 51-84
  • Publisher: Burlington, MA, USA : Academic Press
  • URL: ISBN: 978-0-12-385855-9.
• [Remarks]
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/contribution.html
• [Patent(Industrial Property Rights)] 抗ヒトCD26モノクローナル抗体又はその抗原結合性断片 (2013)
  • Inventor(s): 大沼圭、波多野良、山田健人、森本幾夫
  • Industrial Property Rights Holder: 順天堂大学、キッセイ薬品工業
  • Industrial Property Number: 特願, 2013-158533
  • Filing Date: 2013-07-31
• [Patent(Industrial Property Rights)] MERSコロナウイルス感染症予防治療剤 (2013)
  • Inventor(s): 大沼圭、森本幾夫
  • Industrial Property Rights Holder: 順天堂大学
  • Industrial Property Number: 特願, 2013-187124
  • Filing Date: 2013-09-17