Th17-suppressing novel regulatory T cells and the use thereof

• Project/Area Number: 25460592
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Kagawa University
• Principal Investigator: Niki Toshiro 香川大学, 医学部, 助教 (40558508)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: ガレクチン / 自己免疫疾患 / ガン / アレルギー / 免疫制御 / ガレクチン９ / 糖鎖 / レクチン / 炎症 / 免疫 / 感染症 / 制御性T細胞

Outline of Final Research Achievements

Galectin-9 an endogenous immunomodulator can normalize skewed immune balance and hence is supposed to have utilities for the treatment of refractory diseases including autoimmunities and cancers. We have been seeing galectin-9 as a promising seed molecule and have been studying it to elucidate the therapeutic mode-of-action and an appropriate disease indication for IND application. Through this research, we uncovered that the mode-of-action included signal transduction through a TNF-receptor superfamily 4-1BB and that the administration of galectin-9 demonstrated unprecedented therapeutic activities including 1)cytotoxicity in drug-resistant colon cancer cells by inducing incomplete autophagy, 2)drastic improvement of survival in an ischemia-reperfusion injury model in mice, 3)reactivation HIV from latently-infected cells and introduction of mutation in the viral genome. These results were summarized in research or patent articles and accepted for publications.

Research Products

• [Int'l Joint Research] University of Hawai'i/Oregon National Primate Research Center/Blood Systems Research Institute(米国)
• [Int'l Joint Research] Institut Gustave Roussy(France)
• [Int'l Joint Research] University of Groningen(Netherlands)
• [Journal Article] Development of Point-of-Care Testing for Disaster-Related Infectious Diseases (2016)
  • Author(s): Hattori T, Chagan-Yasutan H, Shiratori B, Egawa S, Izumi T, Kubo T, Nakajima C, Suzuki Y, Niki T, Alisjahbana B, Telan E.
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 238 Issue: 4 Pages: 287-293
  • DOI: 10.1620/tjem.238.287
  • NAID: 130005138757
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed
• [Journal Article] Galectin-9: An anticancer molecule for gallbladder carcinoma. (2016)
  • Author(s): Tadokoro T, Morishita A, Fujihara S, Iwama H, Niki T, Fujita K, Akashi E, Mimura S, Oura K, Sakamoto T, Nomura T, Tani J, Miyoshi H, Yoneyama H, Himoto T, Hirashima M, Masaki T.
  • Journal Title: Int J Oncol Volume: 48 Issue: 3 Pages: 1165-1174
  • DOI: 10.3892/ijo.2016.3347
  • Peer Reviewed / Open Access
• [Journal Article] Galectin-9 suppresses the proliferation of gastric cancer cells in vitro. (2016)
  • Author(s): Takano J, Morishita A, Fujihara S, Iwama H, Kokado F, Fujikawa K, Fujita K, Chiyo T, Tadokoro T, Sakamoto T, Nomura T, Tani J, Miyoshi H, Yoneyama H, Kobara H, Mori H, Niki T, Hirashima M, Masaki T.
  • Journal Title: Oncol Rep Volume: 35 Issue: 2 Pages: 851-860
  • DOI: 10.3892/or.2015.4452
  • Peer Reviewed / Open Access
• [Journal Article] Acute Liver Failure Study Group. Association Between Plasma Level of Galectin-9 and Survival of Patients With Drug-Induced Acute Liver Failure. (2016)
  • Author(s): Rosen HR, Biggins SW, Niki T, Gralla J, Hillman H, Hirashima M, Schilsky M, Lee WM
  • Journal Title: Clin Gastroenterol Hepatol Volume: 14 Issue: 4 Pages: 606-612
  • DOI: 10.1016/j.cgh.2015.09.040
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evaluation of matricellular proteins in systemic and local immune response to Mycobacterium tuberculosis infection. (2015)
  • Author(s): Hasibuan FM, Shiratori B, Senoputra MA, Chagan-Yasutan H, Koesoemadinata RC, Apriani L, Takahashi Y, Niki T, Alisjahbana B, Hattori T.
  • Journal Title: Microbiol Immunol Volume: 59 Issue: 10 Pages: 623-632
  • DOI: 10.1111/1348-0421.12320
  • Peer Reviewed
• [Journal Article] Galectin-9 suppresses cholangiocarcinoma cell proliferation by inducing apoptosis but not cell cycle arrest. (2015)
  • Author(s): Kobayashi K, Morishita A, Iwama H, Fujita K, Okura R, Fujihara S, Yamashita T, Fujimori T, Kato K, Kamada H, Niki T, Hirashima M, Okano K, Suzuki Y, Masaki T.
  • Journal Title: Oncol Rep Volume: 34 Issue: 4 Pages: 1761-1770
  • DOI: 10.3892/or.2015.4197
  • Peer Reviewed
• [Journal Article] The epithelial polarity regulator LGALS9/galectin-9 induces fatal frustrated autophagy in KRAS mutant colon carcinoma that depends on elevated basal autophagic flux. (2015)
  • Author(s): Wiersma VR, de Bruyn M, Wei Y, van Ginkel RJ, Hirashima M, Niki T, Nishi N, Zhou J, Pouwels SD, Samplonius DF, Nijman HW, Eggleton P, Helfrich W, Bremer E.
  • Journal Title: Autophagy Volume: 11 Issue: 8 Pages: 1373-1388
  • DOI: 10.1080/15548627.2015.1063767
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of Exogenous Galectin-9 on Human T Cells: CONTRIBUTION OF THE T CELL RECEPTOR COMPLEX TO ANTIGEN-INDEPENDENT ACTIVATION BUT NOT TO APOPTOSIS INDUCTION. (2015)
  • Author(s): Lhuillier C, Barjon C, Niki T, Gelin A, Praz F, Morales O, Souquere S, Hirashima M, Wei M, Dellis O, Busson P.
  • Journal Title: J Biol Chem Volume: 290 Issue: 27 Pages: 16797-16811
  • DOI: 10.1074/jbc.m115.661272
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The protective function of galectin-9 in liver ischemia and reperfusion injury in mice. (2015)
  • Author(s): Hirofumi Hirao, Yoichiro Uchida, Kentaro Kadono, Hirokazu Tanaka, Toshiro Niki, Akira Yamauchi, Koichiro Hata, Takeshi Watanabe, Hiroaki Terajima, Shinji Uemoto
  • Journal Title: Liver Transplantation Volume: 21 Issue: 7 Pages: 969-981
  • DOI: 10.1002/lt.24159
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] MicroRNA profiles following metformin treatment in a mouse model of non-alcoholic steatohepatitis. (2015)
  • Author(s): Katsura A, Morishita A, Iwama H, Tani J, Sakamoto T, Tatsuta M, Toyota Y, Fujita K, Kato K, Maeda E, Nomura T, Miyoshi H, Yoneyama H, Himoto T, Fujiwara S, Kobara H, Mori H, Niki T, Ono M, Hirashima M, Masaki T.
  • Journal Title: Int J Mol Med Volume: 35 Issue: 4 Pages: 877-884
  • DOI: 10.3892/ijmm.2015.2092
  • Peer Reviewed
• [Journal Article] Galectin-9 suppresses the growth of hepatocellular carcinoma via apoptosis in vitro and in vivo. (2015)
  • Author(s): Fujita K, Iwama H, Sakamoto T, Okura R, Kobayashi K, Takano J, Katsura A, Tatsuta M, Maeda E, Mimura S, Nomura T, Tani J, Miyoshi H, Morishita A, Yoneyama H, Yamana Y, Himoto T, Okano K, Suzuki Y, Niki T, Hirashima M, Masaki T.
  • Journal Title: Int J Oncol. Volume: 46 Issue: 6 Pages: 2419-2430
  • DOI: 10.3892/ijo.2015.2941
  • Peer Reviewed
• [Journal Article] Effect of nasopharyngeal carcinoma-derived exosomes on human regulatory T cells. (2015)
  • Author(s): Mrizak D, Martin N, Barjon C, Jimenez-Pailhes AS, Mustapha R, Niki T, Guigay J, Pancré V, de Launoit Y, Busson P, Moralès O, Delhem N.
  • Journal Title: J Natl Cancer Inst. Volume: 107 Issue: 1 Pages: 1-13
  • DOI: 10.1093/jnci/dju363
  • Peer Reviewed / Open Access
• [Journal Article] Elevated OPN, IP-10, and neutrophilia in loop-mediated isothermal amplification confirmed tuberculosis patients. (2014)
  • Author(s): Shiratori B, Leano S, Nakajima C, Chagan-Yasutan H, Niki T, Ashino Y, Suzuki Y, Telan E, Hattori T.
  • Journal Title: Mediators Inflamm. Volume: 2014 Pages: 1-8
  • DOI: 10.1155/2014/513263
  • Peer Reviewed / Open Access
• [Journal Article] Galectin-9 controls the therapeutic activity of 4-1BB-targeting antibodies. (2014)
  • Author(s): Madireddi S, Eun SY, Lee SW, Nemčovičová I, Mehta AK, Zajonc DM, Nishi N, Niki T, Hirashima M, Croft M.
  • Journal Title: J Exp Med. Volume: 211 Issue: 7 Pages: 1433-1448
  • DOI: 10.1084/jem.20132687
  • Peer Reviewed / Open Access
• [Journal Article] Galectin-9 is rapidly released during acute HIV-1 infection and remains sustained at high levels despite viral suppression even in elite controllers. (2014)
  • Author(s): Tandon R, Chew GM, Byron MM, Borrow P, Niki T, Hirashima M, Barbour JD, Norris PJ, Lanteri MC, Martin JN, Deeks SG, Ndhlovu LC.
  • Journal Title: AIDS Res Hum Retroviruses. Volume: 30 Issue: 7 Pages: 654-664
  • DOI: 10.1089/aid.2014.0004
  • Peer Reviewed
• [Journal Article] Galectin-9 ameliorates anti-GBM glomerulonephritis by inhibiting Th1 and Th17 immune responses in mice. (2014)
  • Author(s): Zhang Q, Luan H, Wang L, He F, Zhou H, Xu X, Li X, Xu Q, Niki T, Hirashima M, Xu G, Lv Y, Yuan J.
  • Journal Title: Am J Physiol Renal Physiol. Volume: 306 Issue: 8 Pages: F822-F832
  • DOI: 10.1152/ajprenal.00294.2013
  • Peer Reviewed / Open Access
• [Journal Article] Galectin-9 enhances cytokine secretion, but suppresses survival and degranulation, in human mast cell line (2014)
  • Author(s): Kojima R, Ohno T, Iikura M, Niki T, Hirashima M, Iwaya K, Tsuda H, Nonoyama S, Matsuda A, Saito H, Matsumoto K, Nakae S
  • Journal Title: PLoS ONE Volume: 9 Issue: 1 Pages: e86106-e86106
  • DOI: 10.1371/journal.pone.0086106
  • Peer Reviewed
• [Journal Article] Galectin-9 prolongs the survival of septic mice by expanding tim-3-expressing natural killer T cells and PDCA-1+ CD11c+ macrophages. (2013)
  • Author(s): Kadowaki T, Morishita A, Niki T, Hara J, Sato M, Tani J, Miyoshi H, Yoneyama H, Masaki T, Hattori T, Matsukawa A, Hirashima M.
  • Journal Title: Crit Care Volume: 17
  • Peer Reviewed
• [Journal Article] Preventive effect of galectin-9 on double-stranded RNA-induced airway hyperresponsiveness in an exacerbation model of mite antigen-induced asthma in mice. (2013)
  • Author(s): Katoh S, Shimizu H, Obase Y, Oomizu S, Niki T, Ikeda M, Mouri K, Kobashi Y, Hirashima M, Oka M.
  • Journal Title: Exp Lung Res Volume: 39 Issue: 10 Pages: 453-462
  • DOI: 10.3109/01902148.2013.850558
  • Peer Reviewed
• [Journal Article] Galectin-9 plasma levels reflect adverse hematological and immunological features in acute dengue virus infection (2013)
  • Author(s): Chagan-Yasutan H1, Ndhlovu LC, Lacuesta TL, Kubo T, Leano PS, Niki T, Oguma S, Morita K, Chew GM, Barbour JD, Telan EF, Hirashima M, Hattori T, Dimaano EM.
  • Journal Title: J Clin Virol Volume: 58(4) Issue: 4 Pages: 635-640
  • DOI: 10.1016/j.jcv.2013.10.022
  • NAID: 120006986004
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cis association of galectin-9 with Tim-3 differentially regulates IL-12/IL-23 expressions in monocytes via TLR signaling (2013)
  • Author(s): Ma CJ1, Li GY, Cheng YQ, Wang JM, Ying RS, Shi L, Wu XY, Niki T, Hirashima M, Li CF, Moorman JP, Yao ZQ
  • Journal Title: PLoS One Volume: 8(8) Issue: 8 Pages: e72488-e72488
  • DOI: 10.1371/journal.pone.0072488
  • Peer Reviewed / Open Access
• [Journal Article] Galectin-9 in combination with rapamycin induces cardiac allograft tolerance in mice. (2013)
  • Author(s): Cai L, Zhou H, Fang Z, Yuan J, Niki T, Hirashima M, He W, Chen ZK.
  • Journal Title: Transplantation Volume: 96 Issue: 4 Pages: 379-386
  • DOI: 10.1097/tp.0b013e31829b07b5
  • Peer Reviewed
• [Journal Article] Galectin-9 activates and expands human T-helper 1 cells. (2013)
  • Author(s): Gooden MJ1, Wiersma VR, Samplonius DF, Gerssen J, van Ginkel RJ, Nijman HW, Hirashima M, Niki T, Eggleton P, Helfrich W, Bremer E.
  • Journal Title: PLoS One Volume: 8(5) Issue: 5 Pages: e65616-e65616
  • DOI: 10.1371/journal.pone.0065616
  • Peer Reviewed / Open Access
• [Journal Article] Galectin-9 ameliorates clinical severity of MRL/lpr lupus-prone mice by inducing plasma cell apoptosis independently of Tim-3. (2013)
  • Author(s): Moritoki M, Kadowaki T, Niki T, Nakano D, Soma G, Mori H, Kobara H, Masaki T, Kohno M, Hirashima M.
  • Journal Title: PLoS One Volume: 8 Issue: 4 Pages: e60807-e60807
  • DOI: 10.1371/journal.pone.0060807
  • Peer Reviewed
• [Journal Article] Galectin-9 in cancer therapy. Recent Pat Endocr Metab Immune Drug Discov. (2013)
  • Author(s): Fujihara S, Mori H, Kobara H, Rafiq K, Niki T, Hirashima M, Masaki T.
  • Journal Title: Recent Pat Endocr Metab Immune Drug Discov Volume: 7 Pages: 130-137
  • Peer Reviewed
• [Journal Article] Galectin-9 functionally impairs natural killer cells in humans and mice. (2013)
  • Author(s): Golden-Mason L1, McMahan RH, Strong M, Reisdorph R, Mahaffey S, Palmer BE, Cheng L, Kulesza C, Hirashima M, Niki T, Rosen HR.
  • Journal Title: J Virol Volume: 87(9): Issue: 9 Pages: 4835-4845
  • DOI: 10.1128/jvi.01085-12
  • Peer Reviewed
• [Presentation] Potential functions of galectin-9 in mucosal immunity. (2015)
  • Author(s): Niki T, Fukunaga H, Natori T, Hara A,Takeda K, Ezaki T.
  • Organizer: 日本細菌学会国際シンポジウム
  • Place of Presentation: 長良川国際会議場
  • Year and Date: 2015-03-26