Development of novel immunotherapy by using of human iPS cells of an antigen-specific T-cell origin

• Project/Area Number: 22659058
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: General medical chemistry
• Research Institution: The University of Tokyo
• Principal Investigator: NAKAUCI Hiromitsu 東京大学, 医科学研究所, 教授 (40175485)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥3,090,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2010: ¥1,400,000 (Direct Cost: ¥1,400,000)
• Keywords: 抗原特異的T細胞 / iPS細胞 / 幹細胞 / T細胞の分化誘導

Research Abstract

Adoptive immunotherapy with antigen-specific T cells expressing a limited TCR repertoire is a promising approach to fighting various types of cancer and chronic viral infections ; however, the effectiveness of this therapy declines due to exhaustion of the antigen-specific T cells. To overcome this problem, we have explored the potential of induced pluripotent stem(iPS) cell technology and have generated T cell-derived iPS(T-iPS) cells. Furthermore, we have succeeded in redifferentiating T-iPS cells into T lineage cells. As was expected, the invariance of the antigen specificity was evidenced by the fact that the TCR gene rearrangement patterns in the redifferentiated T lineage cells were identical to those in the original T cell. These findings suggest that regeneration of antigen-specific immune systems using iPS cell technology will shed new light on the field of adoptive immunotherapy.

Research Products

• [Journal Article] Lethal myelofibrosis induced by Bmi1-deficient hematopoietic cells unveils a tumor suppressor function of the polycomb group genes (2012)
  • Author(s): Oguro H, Yuan J, Tanaka S, Miyagi S, Mochizuki-Kashio M, Ichikawa H, Yamazaki S, Koseki H, Nakauchi H, Iwama A
  • Journal Title: J Exp Med Volume: 209 Pages: 445-54
  • Peer Reviewed
• [Journal Article] A Differentiation Checkpoint Limits Hematopoietic Stem Cell Self-Renewal in Response to DNA Damage (2012)
  • Author(s): Wang J, Sun Q, Morita Y, Jiang H, Gross A, Lechel A, Hildner K, Guachalla LM, Gompf A, Hartmann D, Schambach A, Wuestefeld T, Dauch D, Schrezenmeier H, Hofmann WK, Nakauchi H, Ju Z, Kestler HA, Zender L, Rudolph KL
  • Journal Title: Cell Volume: 148 Issue: 5 Pages: 1001-1014
  • DOI: 10.1016/j.cell.2012.01.040
  • Peer Reviewed
• [Journal Article] Generation of germline-competent rat induced pluripotent stem cells (2011)
  • Author(s): Hamanaka S
  • Journal Title: PLoS ONE Volume: 6 Issue: 7 Pages: e22008-e22008
  • DOI: 10.1371/journal.pone.0022008
  • Peer Reviewed
• [Journal Article] Development of defective and persistent sendai virus vector : a unique gene delivery/expression system ideal for cell reprogramming (2011)
  • Author(s): Nishimura K, Sano M, Ohtaka M, Furuta B, Umemura Y, Nakajima Y, Ikehara Y, Kobayashi T, Segawa H, Takayasu S, Sato H, Motomura K, Uchida E, Kanayasu-Toyoda T, Asashima M, Nakauchi H, Yamaguchi T, Nakanishi M
  • Journal Title: J Biol Chem Volume: 11 Issue: 6 Pages: 476-71
  • DOI: 10.1074/jbc.m110.183780
  • Peer Reviewed
• [Journal Article] Frequent pathway mutations of splicing machinery in myelodysplasia (2011)
  • Author(s): Kenichi Yoshida
  • Journal Title: Nature Volume: 478 Issue: 7367 Pages: 64-69
  • DOI: 10.1038/nature10496
  • Peer Reviewed
• [Journal Article] Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche (2011)
  • Author(s): Yamazaki S, Ema H, Karlsson G, Yamaguchi T, Miyoshi H, Shioda S, Taketo MM, Karlsson S, Iwama A, Nakauchi H
  • Journal Title: Cell Volume: 147 Issue: 5 Pages: 1146-1158
  • DOI: 10.1016/j.cell.2011.09.053
  • Peer Reviewed
• [Journal Article] Development of defective and persistent sendai virus vector : a unique gene delivery/expression system ideal for cell reprogramming. (2011)
  • Author(s): Nishimura K, Sano M, Ohtaka M, Furuta B, Umemura Y, Nakajima Y, Ikehara T, Kobayashi T, Segawa H, Takayasu S, Sato H, Motomura K, Uchida E, Kanayasu-Toyoda T, Asashima M, Nakauchi H, Yamaguchi T, Nakanishi M.
  • Journal Title: J Biol Chem Volume: 11 Pages: 4760-71
  • Peer Reviewed
• [Journal Article] Reduction of N-Glycolylneuraminic Acid in Human Induced Pluripotent Stem Cells Generated or Cultured under Feeder-and Serum-Free Defined Conditions (2010)
  • Author(s): Hayashi Y, Chan T, Warashina M, et al.(14名9番目)
  • Journal Title: PLoS One Volume: 5 Issue: 11 Pages: e14099-e14099
  • DOI: 10.1371/journal.pone.0014099
  • Peer Reviewed
• [Journal Article] Transient activation of c-MYC expression is critical for efficient platelet generation from human induced pluripotent stem cells (2010)
  • Author(s): Takayama N, Nishimura S, Nakamura S, et al.(16名16番目)
  • Journal Title: Journal of Experimental Medicine Volume: 207 Issue: 13 Pages: 2817-2830
  • DOI: 10.1084/jem.20100844
  • Peer Reviewed
• [Journal Article] Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells (2010)
  • Author(s): Kobayashi T
  • Journal Title: Cell Volume: 142 Issue: 5 Pages: 787-799
  • DOI: 10.1016/j.cell.2010.07.039
  • Peer Reviewed
• [Journal Article] Reprogramming adult hematopoietic cells (2010)
  • Author(s): Kaneko S, Otsu M, Nakauchi H
  • Journal Title: Curr Opin Hematol Volume: 17 Issue: 4 Pages: 271-5
  • DOI: 10.1097/moh.0b013e32833a25ee
  • Peer Reviewed
• [Journal Article] Downregulation of ZEB1 and overexpression of Smad7 contribute to resistance to TGF-β1-mediated growth suppression in adult T-cell leukemia/lymphoma (2010)
  • Author(s): Nakahata, S., Yamazaki, H., Nakauchi, H., Morishita, K
  • Journal Title: Oncogene Volume: 29 Issue: 29 Pages: 4157-4159
  • DOI: 10.1038/onc.2010.172
  • Peer Reviewed
• [Journal Article] Downregulation of ZEB1 and overexpression of Smad7 contribute to resistance to TGF-beta 1-mediated growth suppression in adult T-cell leukemia/lymphoma. (2010)
  • Author(s): Nakahata S, Yamazaki S, Nakauchi H, Morishita K.
  • Journal Title: Oncogene Volume: 29 Pages: 4157-69
  • Peer Reviewed
• [Journal Article] Reprogramming adult hematopoietic cells. (2010)
  • Author(s): Kaneko S, Otsu M, Nakauchi H.
  • Journal Title: Curr Opin Hematol Volume: 17 Pages: 271-5
  • Peer Reviewed
• [Journal Article] Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells. (2010)
  • Author(s): Kobayashi T, Yamaguchi T, Hamanaka S, Kato-Itoh M, Yamazaki Y, Ibata M, Sato H, Lee YS, Usui J, Knisely AS, Hirabayashi M, Nakauchi H.
  • Journal Title: Cell Volume: 3 Pages: 787-99
  • Peer Reviewed
• [Journal Article] Transient activation of c-MYC expression is critical for efficient platelet generation from human induced pluripotent stem cells. (2010)
  • Author(s): Takayama N, Nishimura S, Nakamura S, Shimizu T, Ohnishi R, Endo H, Yamaguchi T, Otsu M, Nishimura K, Nakanishi M, Sawaguchi A, Nagai R, Takahashi K, Yamanaka S, Nakauchi H, Eto K.
  • Journal Title: J Exp Med Volume: 20 Pages: 2817-30
  • Peer Reviewed
• [Journal Article] Reduction of N-Glycolylneuraminic Acid in Human Induced Pluripotent Stem Cells Generated or Cultured under Feeder- and Serum-Free Defined Conditions. (2010)
  • Author(s): HayashiY, Chan T, Warashina M, Fukuda M, Ariizumi T, Okabayashi K, Takayama N, Otsu M, Eto K, Furue MK, Michiue T, Ohnuma K, Nakauchi H, Asashima M.
  • Journal Title: PLoS One Volume: 23
  • Peer Reviewed
• [Presentation] Generation of functional organs from pluripotent stem cells (2011)
  • Author(s): Hiromitsu Nakauchi
  • Organizer: Cold Spring Harbor Conferences Asia & ISSCR
  • Place of Presentation: Tehran, Iran
  • Year and Date: 2011-10-26
• [Presentation] Generation of functional organs from pluripotent stem cells (2011)
  • Author(s): Hiromitsu Nakauchi
  • Organizer: Cold Spring Harbor Conferences Asia & ISSCR
  • Place of Presentation: 蘇州、中国(招待講演)
  • Year and Date: 2011-10-26
• [Presentation] Generation of functional organs from iPS cells (2011)
  • Author(s): Hiromitsu Nakauchi
  • Organizer: 12th International Congress on Reproductive Biomedicine & 7th International Congress on Stem Cell Biology and Technology
  • Place of Presentation: Suzhou, China
  • Year and Date: 2011-09-07
• [Presentation] Generation of functional organs from iPS cells (2011)
  • Author(s): Hiromitsu Nakauchi
  • Organizer: 12th International Congress on Reproductive Biomedicine & 7th International Congress on Stem Cell Biology and Technology
  • Place of Presentation: Tehran, Iran(招待講演)
  • Year and Date: 2011-09-07
• [Presentation] Non-myelinating Schwann cells in the mouse bone marrow niche maintain hematopoietic stem cell hibernation through TGF-b signaling (2011)
  • Author(s): Hiromitsu Nakauchi
  • Organizer: The Oklahoma Center for Adult Stem Cell Research(OCASCR)
  • Place of Presentation: Oklahoma, USA
  • Year and Date: 2011-06-14
• [Presentation] Non-myelinating Schwann cells in the mouse bone marrow niche maintain hematopoietic stem cell hibernation through TGF-b signaling (2011)
  • Author(s): Hiromitsu Nakauchi
  • Organizer: The Oklahoma Center for Adult Stem Cell Research (OCASCR)
  • Place of Presentation: Oklahoma, USA(招待講演)
  • Year and Date: 2011-06-14
• [Presentation] Generation of Rat Pancreas in Mouse : toward the next generation of regenerative medicine (2011)
  • Author(s): Hiromitsu Nakauchi
  • Organizer: ESHG Symposium
  • Place of Presentation: Amsterdam, Holland
  • Year and Date: 2011-05-29
• [Presentation] Generation of Rat Pancreas in Mouse : toward the next generation of regenerative medicine (2011)
  • Author(s): Hiromitsu Nakauchi
  • Organizer: ESHG Symposium
  • Place of Presentation: Amsterdam, Holland(招待講演)
  • Year and Date: 2011-05-29
• [Presentation] Replicative senescence of hematopoietic stem cells after single cell transplantation (2011)
  • Author(s): Hiromitsu Nakauchi
  • Organizer: 3rd Else Kroner-Fresenius Symposium on Molecular Mechanisms of Stem Cell Aging
  • Place of Presentation: Ulm, Germany
  • Year and Date: 2011-05-20
• [Presentation] Replicative senescence of hematopoietic stem cells after single cell transplantation (2011)
  • Author(s): Hiromitsu Nakauchi
  • Organizer: 3rd Else Kroner-Fresenius Symposium on Molecular Mechanisms of Stem Cell Aging
  • Place of Presentation: Ulm, Germany(招待講演)
  • Year and Date: 2011-05-20
• [Presentation] Non-myelinating schwann cells in the mouse bone marrow niche maintain hematopoietic stem cell hibernation through TGF-beta signaling (2011)
  • Author(s): Hiromitsu Nakauchi
  • Organizer: Keystone Symposia
  • Place of Presentation: Keystone, USA
  • Year and Date: 2011-04-01
• [Presentation] Non-myelinating schwann cells in the mouse bone marrow niche maintain hematopoietic stem cell hibernation through TGF-beta signaling (2011)
  • Author(s): Hiromitsu Nakauchi
  • Organizer: Keystone Symposia
  • Place of Presentation: Keystone, USA(招待講演)
  • Year and Date: 2011-04-01
• [Patent(Industrial Property Rights)] 抗原特異的T細胞の製造方法 (2012)
  • Inventor(s): 中内啓光、金子新、西村聡修
  • Industrial Property Rights Holder: 東京大学
  • Industrial Property Number: 2012-116639
  • Filing Date: 2012-05-22
  • Overseas
• [Patent(Industrial Property Rights)] 多能性幹細胞からの血液細胞分化に関する培養方法 (2011)
  • Inventor(s): 佐野進弥、江藤浩之、高山直也、中内啓光
  • Industrial Property Rights Holder: 東京大学、テルモ株式会社
  • Filing Date: 2011-09-09
  • Overseas
• [Patent(Industrial Property Rights)] 誘導型多能性幹細胞の製造方法 (2011)
  • Inventor(s): 中内啓光,大津真,高山直也,安東赫
  • Industrial Property Rights Holder: 東京大学
  • Filing Date: 2011-06-15
  • Overseas
• [Patent(Industrial Property Rights)] Method for Immunological Reconstitution using Pluripotent Stem Cells (2011)
  • Inventor(s): 中内啓光、金子新、西村聡修
  • Industrial Property Rights Holder: 東京大学
  • Filing Date: 2011-02-03
  • Overseas
• [Patent(Industrial Property Rights)] 誘導型多能性幹細胞の製造方法 (2011)
  • Inventor(s): 中内啓光, 大津真, 高山直也, 安東赫
  • Industrial Property Rights Holder: 東京大学
  • Filing Date: 2011-06-15
  • Overseas
• [Patent(Industrial Property Rights)] 多能性幹細胞からの血液細胞分化に関する培養方法 (2011)
  • Inventor(s): 佐野進弥、江藤浩之、高山直也、中内啓光
  • Industrial Property Rights Holder: 東京大学テルモ株式会社
  • Filing Date: 2011-09-09
  • Overseas