Basic Approach for the Development of Molecular Target Therapy for Autoimmune Diseases and Immune-Mediated Disorders.

2009 Fiscal Year Final Research Report

• Project/Area Number: 17109011
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: The University of Tokyo
• Principal Investigator: MORIMOTO Chikao The University of Tokyo, 医科学研究所, 教授 (30119028)
• Co-Investigator(Kenkyū-buntansha): HOSONO Osamu 東京大学, 医科学研究所, 助教 (50190210) ; IWATA Satoshi 東京大学, 医科学研究所, 特任講師 (00396871) ; YAMOCHI Tadanori 東京大学, 医科学研究所, 産学官連携研究員 (80306844) ; KAWASAKI Hiroshi 東京大学, 医科学研究所, 助教 (80280957) ; OHNUMA Kei (10396872) ; IKEDA Teturo 東京大学, 医科学研究所, 特任研究員 (10360489)
• Project Period (FY): 2005 – 2009
• Keywords: 膠原病 / リウマチ学 / 臨床免疫学

Research Abstract

We have identified caveolin-1 as the costimulatory ligand for CD26. The 82-101th amino acid (a・a) of caveolin-1 bound to the 201-211th a・a of CD26 with the DPPIV catalytic site of 630^<th> a・a, Serine. Moreover, we found that cytoplasmic tail of CD26 interacts with CARMA-1 in T cells, resulting in the induction of costimulatory signal. After injection of human PBL into SCID mice, the symptom of xeno-GVHD has been induced and human T cells play a role in pathophysiology of x-GVHD as effectors. Treatment of these x-GVHD mice with humanized CD26 antibody resulted in improvement of the symptom of x-GVHD, suggesting that anti-CD26 treatment leads to the effective treatment of human immune-mediated diseases such as autoimmune disorders and GVHD after allo-BMT.

Research Products

• [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
• [Journal Article] Microscopic polyangiitis initiated with liver dysfunction, calf pain and fever of unknown origin (2009)
  • Author(s): Ohnuma K, Hosono O, Katayose T, Yoshikawa N, Kawasaki H, Fujii T, Oyaizu N, Tanaka H, Morimoto C.
  • Journal Title: Rheumatol Int.
• [Journal Article] CD26 expression on T cell lines increases SDF-1-alpha-mediated invasion (2009)
  • Author(s): Havre PA, Abe M, Urasaki Y, Ohnuma K, Morimoto C, Dang NH.
  • Journal Title: Br J Cancer. 101 Pages: 983-91
• [Journal Article] Caveolin-1 is a novel immunohistochemical marker to differentiate epithelioid mesothelioma from lung adenocarcinoma (2009)
  • Author(s): Amatya VJ, Takeshima Y, Kohno H, Kushitani K, Yamada T, Morimoto C, Inai K.
  • Journal Title: Histopathology 55 Pages: 10-9
• [Journal Article] The CD70-CD27 interaction during the stimulation with dendritic cells promotes naive CD4+ T cells to develop into T cells producing a broad array of immunostimulatory cytokines in humans (2009)
  • Author(s): Hashimoto-Okada M, Kitawaki T, Kadowaki N, Iwata S, Morimoto C, Hori T, Uchiyama T.
  • Journal Title: Int Immunol. 21 Pages: 891-904
• [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. 386 Pages: 327-32
• [Journal Article] Histamine Hl-receptor antagonists 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. 157 Pages: 27-34
• [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. Pages: 9-17
• [Journal Article] CD90 and CD110 correlate with cancer stem cell potentials in human T-acute lymphoblastic leukemia cells (2009)
  • Author(s): Yamazaki H, Nishida H, Iwata S, Dang NH, Morimoto C.
  • Journal Title: Biochem Biophys Res Commun. 383 Pages: 172-7
• [Journal Article] SHP-2 inhibits tyrosine phosphorylation of Cas-L and regulates cell migration (2009)
  • Author(s): Yo K, Iwata S, Hashizume Y, Kondo S, Nomura S, Hosono O, Kawasaki H, Tanaka H, Dang NH, Morimoto C.
  • Journal Title: Biochem Biophys Res Commun. 382 Pages: 210-4
• [Journal Article] CD9 correlates with cancer stem cell potentials in human B-acute lymphoblastic leukemia cells (2009)
  • Author(s): Nishida H, Yamazaki H, Yamada T, Iwata S, Dang NH, Inukai T, Sugita K, Ikeda Y, Morimoto C.
  • Journal Title: Biochem Biophys Res Commun. 382 Pages: 57-62
• [Journal Article] An adult case of Henoch-Schonlein purpura complicating common peroneal nerve mononeuropathy (2009)
  • Author(s): Ohnuma K, Hosono O, Kawasaki H, Yoshikawa N, Katayose T, Oyaizu N, Tanaka H, Morimoto C.
  • Journal Title: Mod Rheumatol. 19 Pages: 73-9
• [Journal Article] Revisiting an old acquaintance : CD26 and its molecular mechanisms in T cell function (2008)
  • Author(s): Ohnuma K, Dang NH, Morimoto C.
  • Journal Title: Trends Immunol. 29 Pages: 295-301
• [Journal Article] Role of CD26/dipeptidyl peptidase IV in human T cell activation and function (2008)
  • Author(s): Ohnuma K, Takahashi N, Yamochi T, Hosono O, Dang NH, Morimoto C.
  • Journal Title: Front Biosci. 13 Pages: 2299-310
• [Journal Article] Comparative study of regulatory T cell function of human CD25CD4 T cells from thymocytes, cord blood, and adult peripheral blood (2008)
  • Author(s): Fujimaki W, Takahashi N, Ohnuma K, Nagatsu M, Kurosawa H, Yoshida S, Dang NH, Uchiyama T, Morimoto C.
  • Journal Title: Clin Dev Immunol. 2008 Pages: 305859
• [Journal Article] Tissue- and context-dependent modulation of hormonal sensitivity of glucocorticoid-responsive genes by hexamethylene bisacetamide-inducible protein 1 (2008)
  • Author(s): Shimizu N, Yoshikawa N, Wada T, Handa H, Sano M, Fukuda K, Suematsu M, Sawai T, Morimoto C, Tanaka H.
  • Journal Title: Mol Endocrinol. 22 Pages: 2609-23
• [Journal Article] Fibronectin promotes cell proliferation of human pre-B cell line via its interactions with VLA-4 and VLA-5 (2008)
  • Author(s): Harima A, Nakaseko C, Yokota A, Kitagawa M, Morimoto C, Harigaya K, Saito Y.
  • Journal Title: Hematology 13 Pages: 236-43
• [Journal Article] Role of the hinge region of glucocorticoid receptor for HEXIM1-mediated transcriptional repression (2008)
  • Author(s): Yoshikawa N, Shimizu N, Sano M, Ohnuma K, Iwata S, Hosono O, Fukuda K, Morimoto C, Tanaka H.
  • Journal Title: Biochem Biophys Res Commun. 371 Pages: 44-9
• [Journal Article] SSA/Ro52 autoantigen interacts with Dcp2 to enhance its decapping activity (2008)
  • Author(s): Yamochi T, Ohnuma K, Hosono O, Tanaka H, Kanai Y, Morimoto C.
  • Journal Title: Biochem Biophys Res Commun. 370 Pages: 195-9
• [Journal Article] The role of CD26/dipeptidyl peptidase IV in cancer (2008)
  • Author(s): Havre PA, Abe M, Urasaki Y, Ohnuma K, Morimoto C, Dang NH.
  • Journal Title: Front Biosci. 13 Pages: 1634-45
• [Journal Article] Stem cell properties and the side population cells as a target for interferon-alpha in adult T-cell leukemia/lymphoma (2007)
  • Author(s): Kayo H, Yamazaki H, Nishida H, Dang NH, Morimoto C.
  • Journal Title: Biochem Biophys Res Commun. 364 Pages: 808-14
• [Journal Article] Could serum antibody to poly (ADP-ribose) and/or histone H1 be marker for senile dementia of Alzheimer type? (2007)
  • Author(s): Kanai Y, Akatsu H, Iizuka H, Morimoto C.
  • Journal Title: Ann N Y Acad Sci. 1109 Pages: 338-44
• [Journal Article] Humanized Anti-CD26 monoclonal antibody as a treatment for malignant mesothelioma tumors (2007)
  • Author(s): Inamoto T, Yamada T, Ohnuma K, Kina S, Takahashi N, Yamochi T, Inamoto S, Katsuoka Y, Hosono O, Tanaka H, Dang NH, Morimoto C.
  • Journal Title: Clin Cancer Res. 13 Pages: 4191-200
• [Journal Article] Transcriptional upregulation of ipas gene expression by HIF-1 : A negative feedback regulatory circuit in HIF-1-mediated signaling in hypoxic cells (2007)
  • Author(s): Makino Y, Uenishi R, Okamoto K, Isoe T, Hosono O, Tanaka H, Kanopka A, Poellinger L, Haneda M, Morimoto C.
  • Journal Title: J Biol Chem. 282 Pages: 14073-82
• [Journal Article] Caveolin-1 triggers T-cell activation via CD26 in association with CARMA1 (2007)
  • Author(s): Ohnuma K, Uchiyama M, Yamochi T, Nishibashi K, Hosono O, Takahashi N, Kina S, Tanaka H, Lin X, Dang NH, Morimoto C.
  • Journal Title: J Biol Chem. 282 Pages: 10117-31
• [Journal Article] Knockdown of XAB2 enhances all-trans retinoic acid-induced cellular differentiation in all-trans retinoic acid-sensitive and -resistant cancer cells (2007)
  • Author(s): Ohnuma-Ishikawa K, Morio T, Yamada T, Sugawara Y, Ono M, Nagasawa M, Yasuda A, Morimoto C, Ohnuma K, Dang NH, Hosoi H, Verdin E, Mizutani S.
  • Journal Title: Cancer Res. 67 Pages: 1019-29
• [Journal Article] Crk-associated substrate lymphocyte type regulates transforming growth factor-beta signaling by inhibiting Smad6 and Smad7 (2007)
  • Author(s): Inamoto S, Iwata S, Inamoto T, Nomura S, Sasaki T, Urasaki Y, Hosono O, Kawasaki H, Tanaka H, Dang NH, Morimoto C.
  • Journal Title: Oncogene 26 Pages: 893-904
• [Journal Article] Anti-CD26 monoclonal antibody-mediated G1-S arrest of human renal clear cell carcinoma Caki-2 is associated with retinoblastoma substrate dephosphorylation, cyclin-dependent kinase 2 reduction, p27 (kipl) enhancement, and disruption of binding to the extracellular matrix (2006)
  • Author(s): Inamoto T, Yamochi T, Ohnuma K, Iwata S, Kina S, Inamoto S, Tachibana M, Katsuoka Y, Dang NH, Morimoto C.
  • Journal Title: Clin Cancer Res. 12 Pages: 3470-7
• [Journal Article] Nedd9 protein, a Cas-L homologue, is upregulated after transient global ischemia in rats : possible involvement of Nedd9 in the differentiation of neurons after ischemia (2005)
  • Author(s): Sasaki T, Iwata S, Okano HJ, Urasaki Y, Hamada J, Tanaka H, Dang NH, Okano H, Morimoto C.
  • Journal Title: Stroke 36 Pages: 2457-62
• [Journal Article] CD26 mediates dissociation of Tollip and IRAK-1 from caveolin-1 and induces upregulation of CD86 on antigen-presenting cells (2005)
  • Author(s): Ohnuma K, Yamochi T, Uchiyama M, Nishibashi K, Iwata S, Hosono O, Kawasaki H, Tanaka H, Dang NH, Morimoto C.
  • Journal Title: Mol Cell Biol. 25 Pages: 7743-57
• [Journal Article] CD26 regulates p38 mitogen-activated protein kinase-dependent phosphorylation of integrin betal, adhesion to extracellular matrix, and tumorigenicity of T-anaplastic large cell lymphoma Karpas 299 (2005)
  • Author(s): Sato T, Yamochi T, Yamochi T, Aytac, Ohnuma K, McKee KS, Morimoto C, Dang NH.
  • Journal Title: Cancer Res. 65 Pages: 6950-6
• [Journal Article] CD26 T cells in the pathogenesis of asthma (2005)
  • Author(s): Ohnuma K, Yamochi T, Hosono O, Morimoto C.
  • Journal Title: Clin Exp Immunol. 139 Pages: 13-16
• [Journal Article] Regulation of p38 phosphorylation and topoisomerase IIalpha expression in the B-cell lymphoma line Jiyoye by CD26/dipeptidyl peptidase IV is associated with enhanced in vitro and in vivo sensitivity to doxorubicin (2005)
  • Author(s): Yamochi T, Yamochi T, Aytac U, Sato T, Sato K, Ohnuma K, McKee KS, Morimoto C, Dang NH.
  • Journal Title: Cancer Res. 65 Pages: 1973-83
• [Journal Article] HTLV-I Tax induces and associates with Crk-associated substrate lymphocyte type (Cas-L) (2005)
  • Author(s): Iwata S, Souta-Kuribara A, Yamakawa A, Sasaki T, Shimizu T, Hosono O, Kawasaki H, Tanaka H, Dang NH, Watanabe T, Arima N, Morimoto C.
  • Journal Title: Oncogene 24 Pages: 1262-71
• [Presentation] A Novel Function of CD26-Madiate Costimulation in the Cytotoxic Activity of Human CD8+ T cells in Xenogeneic Chronic Graft-Versus-Host Disease (cGVHD) and GVL Mice Model (2009)
  • Author(s): Hatano R, Ohnuma K, Yamada T, et al, Morimoto C.
  • Organizer: 第51回アメリカ血液学会 (ASH)
  • Place of Presentation: Morial Convention Center (New Orleans, U. S. A.)
  • Year and Date: 2009-12-07
• [Presentation] CD26/DPPIVのヒトT細胞機能と活性化 : ベンチからベッドまで (2009)
  • Author(s): 森本幾夫, 大沼圭
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸国際展示場
  • Year and Date: 2009-10-21
• [Presentation] CD26分子を用いたトランスレーショナルリサーチ (2008)
  • Author(s): 森本幾夫
  • Organizer: 第29回日本炎症・再生医学会教育講演
  • Place of Presentation: 都市センターホテル
  • Year and Date: 2008-07-09
• [Remarks]
  • URL: http://www.ims.u-tokyo.ac.jp/cimmuno/
• [Patent(Industrial Property Rights)] 細胞表面分子CD26を標的とした悪性中皮腫の治療法 (2007)
  • Inventor(s): 森本幾夫, 大沼圭, 稲元輝生
  • Industrial Property Rights Holder: 国立大学法人東京大学
  • Industrial Property Number: 特許特願PCT/JP2008/055344
  • Filing Date: 2007-03-14
• [Patent(Industrial Property Rights)] caveolin-1-Fc γ1融合タンパク質及びその使用 (2006)
  • Inventor(s): 森本幾夫, 大沼圭
  • Industrial Property Rights Holder: 国立大学法人東京大学
  • Industrial Property Number: 特許特願2006-351154
  • Filing Date: 2006-12-27
• [Patent(Industrial Property Rights)] 免疫調整剤のスクリーニング方法 (2006)
  • Inventor(s): 森本幾夫, 大沼圭
  • Industrial Property Rights Holder: 国立大学法人東京大学
  • Industrial Property Number: 特許特願2006-351173
  • Filing Date: 2006-12-17