活性化NKT細胞によるがん転移抑制機構と臨床応用に関する基礎研究

• Project/Area Number: 13218016
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Chiba University
• Principal Investigator: 中山 俊憲 千葉大学, 大学院・医学研究院, 教授 (50237468)
• Project Period (FY): 2001 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥35,700,000 (Direct Cost: ¥35,700,000); Fiscal Year 2004: ¥9,100,000 (Direct Cost: ¥9,100,000); Fiscal Year 2003: ¥9,100,000 (Direct Cost: ¥9,100,000); Fiscal Year 2002: ¥9,000,000 (Direct Cost: ¥9,000,000); Fiscal Year 2001: ¥8,500,000 (Direct Cost: ¥8,500,000)
• Keywords: NKT細胞 / 免疫細胞療法 / αGalCer / NKG2I / NKG21 / 肺癌 / NKレセプター / 細胞治療

Research Abstract

マウス及びヒトのNKT細胞は、糖脂質αガラクトシルセラミド、α-GalCerで活性化すると強い抗腫瘍作用を発揮する。従来の免疫系と全く異なるNKT細胞免疫系の抗腫瘍メカニズムを解明し、NKT細胞免疫系に焦点を絞ったがん免疫療法の開発に関する基礎研究を行うことを目的とする。動物実験や肺癌患者の細胞を用いた研究で、α-GalCerをパルスした自己樹状細胞を用いた細胞治療によって、肺癌の肺転移に対して治療効果が期待できる、ということが明らかになってきた。本年度は、GMP基準を遵守した細胞調整のプロトコールを確立し、GMPグレードのα-GalCer(キリンビールより供与)を用いてin vitroで活性化した活性化NKT細胞を用いてphase I相当の臨床研究を行った。2段階のdose-escalation studyを行い、経過観察を行った結果、いずれの場合も重特な有害事象は認めなかった。一人の患者の治療と経過観察に2ヶ月以上、レベルの上昇にはそれ以前のレベルでの安全性の確認と、細胞治療効果安全性評価委員会の承認という厳格なプロセスをへた上で臨床研究を行った。GCP基準を遵守して研究を行った。我々はこの点は非常に重要であると考えている。今後は、平成16年までに行ってきた、糖脂質のαGalCerをパルスした樹状細胞の静脈内投与との併用を考えて、研究を進めていきたい。糖脂質のαGalCerの提示に関して、どのような抗原提示細胞が最も優れているかについても、今後検討していきたい。臨床治療に関しては、安全性を確認するとともに治療の効果を評価するためには症例数の増加が肝要であり、自家NKT細胞療法のPhase IIの探索的研究を進める予定である。

Research Products

• [Journal Article] A phase I study α-galactosylceramide, KRN7000-pulsed dendritic cells in patients with advanced and recurrent non-small cell lung cancer. (2005)
  • Author(s): Ishikawa, A.
  • Journal Title: Clin.Can.Res. (in press)
• [Journal Article] Regulation of Th2 cell differentiation by murine Schnurri-2. (2005)
  • Author(s): Kimura, M.
  • Journal Title: J.Exp.Med. 201 Pages: 397-408
• [Journal Article] Fasdisablingsmallexocyclicpeptidemimetecslimitapoptosisby an unexpected mechanism. (2004)
  • Author(s): Hasegawa, A.
  • Journal Title: Proc.Natl.Acad.Sci.USA 101 Pages: 6599-6604
• [Journal Article] Down-regulation of the invariant Vα14 antigen receptor in NKT cells upon activation. (2004)
  • Author(s): Harada, M.
  • Journal Title: Int.Immunol. 16 Pages: 241-247
• [Journal Article] Genetic alterations in an early-stage pulmonary large cell neuroendocrine carcinoma. (2004)
  • Author(s): Hiroshima, K
  • Journal Title: Cancer 100 Pages: 1190-1198
• [Journal Article] CD28 costimulation controls histone hyperacetylation of the IL-5 gene locus in developing Th2 cells. (2004)
  • Author(s): Inami, M.
  • Journal Title: J.Biol.Chem. 279 Pages: 23123-23133
• [Journal Article] Essential role of GATA3 for the maintenance of Type 2 helper T, Th2 cytokine production and chromatin remodeling at the Th2 cytokine gene loci. (2004)
  • Author(s): Ymashita, M.
  • Journal Title: J.Biol.Chem. 279 Pages: 26983-26990
• [Journal Article] Role of a NK receptor, KLRE-1, in bone marrow allograft rejection : analysis with KLRE-1 deficient mice. (2004)
  • Author(s): Shimizu, E.
  • Journal Title: Blood 104 Pages: 781-783
• [Journal Article] Interleukin, IL-4-independent maintenance of histone modification of the IL-4 gene loci in memory Th2 cells. (2004)
  • Author(s): Yamashita, M.
  • Journal Title: J.Biol.Chem. 279 Pages: 39454-39464
• [Journal Article] Natural killer T cells accelerate atherogenesis in mice. Short title : NKT cells and atherosclerosis in mice. (2004)
  • Author(s): Nakai, Y.
  • Journal Title: Blood 104 Pages: 2051-2059
• [Journal Article] Osteopontin as a mediator of NKT cell function in T cell-mediated liver diseases. (2004)
  • Author(s): Diao, H.
  • Journal Title: Immunity 21 Pages: 539-550
• [Journal Article] STAT6-dependent differentiation and production of IL-5 and IL-13 in murine NK2 cells. (2004)
  • Author(s): Katsumoto, T.
  • Journal Title: J.Immunol. 173 Pages: 4967-4975
• [Publications] Kamata, T.: "src homology 2 domain-containing tyrosine phosphatase SHP-1 controls the development of allergic airway inflammation."J.Clin.Invest.. 111. 109-109 (2003)
• [Publications] Akbari, O.: "Critical role of NKT cells producing IL-4 and IL-13 in the development of allergen induced airway hyperreactivity."Nat.Med.. 6. 582-588 (2003)
• [Publications] Ashcroft, G.S.: "Estrogen modulates cutaneous wound healing by down-regulating macrophage migration inhibitory factor."J.Clin.Invest.. 111. 1308-1309 (2003)
• [Publications] Omori, M.: "CD8 T cell-specific downregulation of histone hyperacetylation and gene activation of the IL-4 gene locus by ROG, repressor of GATA."Immunity. 19. 281-294 (2003)
• [Publications] Nishikawa, H.: "CD4^+ CD25^+ T cells responding to serologically defined sutoantigens suppress antitumor immune responses"Proc.Natl.Acad.Sci.USA. 100. 10902-10906 (2003)
• [Publications] Koike, J.: "Bone marrow allograft rejection mediated by a novel murine NK receptor NKG2L."J.Exp.Med.. 199. 137-143 (2004)
• [Publications] Taniguchi, M.: "The regulatory role of Va14 NKT cells in innate and acquired immune response"Ann.Rev.Imm.. (2003)
• [Publications] Taniguchi, M.: "Ann.Rev.Imm."The regulatory role of Va14 NKT cells in innate and acquired immune response. 31(895) (2003)
• [Publications] Nakayama, T., Kasprowicz, D.J., Yamashita, M., Schubert, L.A., Gillard, G., Kimura, M., Didierlaurent, A., Koseki, H., Ziegler, S.F.: "The generation of mature, single-positive thymocytes in vivo is dysregulated by CD69 blockade or overexpression"J. Immunol. 168. 87-94 (2002)
• [Publications] Gonzalez-Aseguinolaza, G., Van Kaer, L., Bergmann, C.C., Wilson, J.M., Schmieg, J., Kronenberg, M., Nakayama, T., Taniguchi, M., Koezuka, Y., Tsuji, M.: "Natural killer T cell ligand α-galactosylceramide enhances protective immunity induced by malaria vaccines"J. Exp. Med. 195. 617-627 (2002)
• [Publications] Akutsu, Y., Nakayama, T., Harada, M., Kawano, T., Motohashi, S., Shimizu, E., Ito, T., Kamada, N., Saito, T., Matsubara, H., Miyazawa, Y., Ochiai, T., Taniguchi, M.: "Expansion of lung Vα14 NKT cells by administration of α-galactosylceramide-pulsed dendritic cells"Jpn. J. Can. Res. 93. 397-403 (2002)
• [Publications] Motohashi, S., Kobayashi, S., Magara, K., Iizasa, T., Nakayama, T., Fujisawa, T., Taniguchi, M: "Preserved IFN-γ Production of circulating Vα24 NKT cells in primary lung cancer patients"Int. J. Cancer. 102. 159-165 (2002)
• [Publications] Kamata, T., Yamashita, M., Kimura, M., Murata, K., Inami M., Shimizu, C., Sugaya, K., Wang C.-R., Taniguchi, M., Nakayama, T.: "src homology 2 domain-containing tyrosine phosphatase SHP-1 controls the development of allergic airway inflammation"J. Clin. Inv. 111. 109-119 (2003)
• [Publications] Ashcroft, G.S., Mills, S.J., Lei, K., Gibbons, L., Burow, M., Jeong, M-J., Taniguchi, M., Horan, M.A., Wahl, S.M., Nakayama, T.: "Estrogen modulates cutaneous wound healing by down-regulating macrophage migration inhibitory factor"J. Clin. In v.. (in press).
• [Publications] Taniguchi, M., Harada, M., Nakayama, T., Wakao, H.: "Ann. Rev. Imm."The regulatory role of Vα14 NKT cells in innate and acquired immune response(in press).
• [Publications] Shin, T. et al.: "Inhibition of tumor metastasis by adoptive cell transfer of IL-12-activated Vα14 NKT cells"Int. J. of Cancer. 91. 523-528 (2001)
• [Publications] Seino, K. et al.: "Requirement for NKT cells in the induction of allograft tolerance"Proc. Natl. Acad. Sci. USA. 98. 2577-2581 (2001)
• [Publications] Kimura, M. et al.: "Regulation of Th2 cell differentiation by mel-18, a mammalian polycomb group gene"Immunity. 15. 275-287 (2001)
• [Publications] Sharif, S. et al.: "Activation of natural killer T cells by α-galactosylceramide treatment prevents the onset and recurrence of autoimmune Type 1 diabetes"Nature Medicine. 7. 1057-1062 (2001)
• [Publications] Nakayama, T. et al.: "The generation of mature, single-positive thymocytes in vitro is dysregulated by CD69 blockade or overexpression"J. Immunol.. 168. 87-94 (2002)
• [Publications] Suto.A.et al.: "CD4^+ CD25^+ T-cell development is regulated by at least 2 distinct mechanisms"Blood. 99. 555-560 (2002)