成人T細胞白血病(ATL)モデル動物を用いた予防法治療法の開発

• Project/Area Number: 18659115
• Research Category: Grant-in-Aid for Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Experimental pathology
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: 長谷川 秀樹 National Institute of Infectious Diseases, 感染病理部, 室長 (30301790)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,300,000 (Direct Cost: ¥3,300,000); Fiscal Year 2007: ¥1,600,000 (Direct Cost: ¥1,600,000); Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
• Keywords: HTLV-1 / ATLL / Tax / NF-κB / IKK-β / chemokine

Research Abstract

(1)NF-κBを標的とした腫瘍の抑制
1)IKK-β阻害剤Bay65-1942によるアポトーシス誘導
Bay65-1942によりNF-κB経路を抑制することで、mATL細胞にアポトーシスを誘導をゲノム断片化の検出及びTUNEL法により調べた。Bay65-1942による濃度依存的なゲノムの断片化を検出した。次にTUNEL法によっても、アポトーシスの初期に生じるDNAの二本鎖切断端の検出を行ったところ、Bay65-1942の濃度依存的にアポトーシス陽性の細胞数が増加していることを確認した。これらの結果から、Bay65-1942はmATL細胞に対してアポトーシスを誘導することが示された。
2)Bay65-1942のin vivoでの腫瘍抑制効果
Bay65-1942のin vivoにおける治療効果をmATL細胞を移植したNOD-SCIDマウスを用いて検討した。その結果、コントロール群では30日目からマウスが死亡を始め、33日目までに全てのマウスが死亡した。一方Bay65-1942を投与した群では濃度依存的な延命効果が認められ、200μg投与群では35日目まで、400μg投与群では40日目まで、800μg投与群に関しては42日目まで生存するマウスが存在し、未投与群と比較して最大で約1.3倍の延命効果を得ることができた。未投与群では末梢血中に白血病細胞を多数認める一方、800μg投与群では、白血病細胞がほとんど認められなかった。また肝臓及び肺組織のHE染色の結果、Bay65-1942未投与群では、いずれの組織でも血管周囲を中心に多数のmATL細胞の浸潤が見られた。一方で、800μg投与群ではいずれの組織でもmATL細胞の浸潤の程度は軽度であった。

Research Products

• [Journal Article] Development of a mucosal vaccine for influenza viruses:preparation for a potential influenza pandemic. (2007)
  • Author(s): Hasegawa H^*, Ichinohe T., Tamura S., Kurata T
  • Journal Title: Expert Review of Vaccines 6(2) Pages: 193-201
• [Journal Article] Prophylactic effects of chitin microparticles(CMP)on highly pathogenic H5N1 influenza virus. (2007)
  • Author(s): Ichinohe T., Nagata N., Strong P., Tamura SI, Takahashi H., Ninomiya A., Imai M., Odagiri T., Tashiro M., Sawa H., Chiba J., Kurata T., Sata T., Hasegawa H^*
  • Journal Title: Journal of Medical Virology 79(6) Pages: 811-819
• [Journal Article] Intranasal immunization with H5N1 vaccine plus Poly I:Poly C_<12>U,a Toll-like receptor agonist,protects mice against homologous and heterologous virus challenge. (2007)
  • Author(s): Ichinohe T., Kawaguchi A., Tamura S., Ninomiya A., Imai M., Itamura S., Odagiri T., Tashiro M., Chiba J., Sata T., Kurata T and Hasegawa H
  • Journal Title: Microbes and Infection 9(11) Pages: 1333-40
• [Journal Article] High Diversity of HHV-8 Molecular Subtypes in the Amazon Region of Brazil:Evidence of an Ancient Human Infection (2007)
  • Author(s): Ishak Mde O., Martins RN, Machado PR, de Souza LL, Machado LF, Azevedo VN, Katano H, Sata T, Hasegawa H., Vallinoto AC, Ishak R.
  • Journal Title: J Med Virol. 79(10) Pages: 1537-44
• [Journal Article] Cross-protection against H5N1 inluenza virus infection afforded by intranasal administration of seasonal trivalent inactivated influenza vaccine (2007)
  • Author(s): Ichinohe T., Tamura S., Kawaguchi A., Ninomiya A., Imai M., Itamura S., Odagiri T., Tashiro M., Takahashi H., Sawa H., Mitchell WM, Strayer DR, Carter WA, Chiba J., Kurata T, Sata T, Hasegawa H^*.
  • Journal Title: J Infect Dis. 196(9) Pages: 1313-20
• [Journal Article] Pathology and virus dispersion in cynomolgus monkeys experimentally inected with severe acute respiratory syndrome coronavirus via different inoculation routes. (2007)
  • Author(s): Nagata N., Iwata N., Hasegawa H., Sato Y., Morikawa S., Saijo M., Itamura S., Saito T., Ami Y., Odagiri T., Tashiro M., Sata T.
  • Journal Title: Int J Exp Pathol. 88(6) Pages: 403-14
• [Journal Article] Development of Thymus-Derived T cell Leukemia/Lymphoma in Mice Transgenic for the Tax gene of Human T-Lymphotropic Virus Type-I (HTLV I). (2006)
  • Author(s): Hasegawa H, Sawa H, Lewis M, Orba Y, Sheehy N, Yamamoto Y, Ichinohe T, Tsunetsugu-Yokota Y, Katano H, Takahashi H, Matsuda J, Sata T, Kurata T, Nagashima K, Hall WW
  • Journal Title: Nature Medicien 12(4) Pages: 466-472
• [Journal Article] Protection against influenza virus infection by intranasal vaccine with Surfclam Powder as a mucosal adjuvant. (2006)
  • Author(s): Ichinohe T, Ito S, Kawaguchi A, Tamura S, Takahashi H, Sawa H, Moriyama M, Chiba J, Kurata T, Sata T, Hasegawa H^*
  • Journal Title: Journal of Medical Virology 78 Pages: 654-963
• [Journal Article] Monkeypox Highly attenuated vaccinia vaccine, LC16m8, that lacks expression of B5R membrane protein protects monkeys from monkeypox (2006)
  • Author(s): Saijo M., Ami Y., Suzaki Y., Nagata N., Iwata N., Hasegawa H., Ogata M., Fukushi S., Mizutani T., Sata T, Kurata T., Kurane I, Morikawa S
  • Journal Title: Journal of Virology 80(11) Pages: 5179-5188
• [Journal Article] Induction of Protective Immunity against Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Infection using Highly Attenuated Recombinant Vaccinia Virus DIs. (2006)
  • Author(s): Ishii K., Hasegawa H., Nagata N., Mizutani T., Morikawa S., Tashiro M., Suzuki T., Taguchi F., Takemori T., Takatsugu-Yokota Y., Miyamura T.
  • Journal Title: Virology 20(8) Pages: 1329-1331
• [Journal Article] Distribution of PrPSc in Cattle with Bovine Spongiform Encephalopathy Slaughtered at Abattoirs in Japan. (2006)
  • Author(s): Iwata N., Sato Y., Higuchi Y., Nohtomi K., Nagata N., Hasegawa H, Tobiume M., Nakamura Y., Hagiwara K., Furuoka H., Horiuchi M., Yamakawa Y., Sata T.
  • Journal Title: Japanese Journal of Infectious Diseases 59(2) Pages: 100-107
• [Journal Article] Tristetraprolin inhibits HIV-1 production by binding to genomic RNA. (2006)
  • Author(s): Maeda M, Sawa H, Tobiume M, Tokunaga K, Hasegawa H, Ichinohe T, Sata T, Moriyama M, Hall WW, Kurata T, Takahashi I
  • Journal Title: Microbes and Infection. 8(11) Pages: 2647-2656
• [Journal Article] Intranasal administration of adjuvant-combined recombinant influenza virus HA vaccine protects mice from the lethal H5N1 virus infection. (2006)
  • Author(s): Asahi-Ozaki Y., Itamura S., Ichinohe T., Strong P., Tamura S., Takahashi H., Sawa H., Moriyama M., Tashiro M., Sata T., Kurata T., Hasegawa H.
  • Journal Title: Microbes and Infection. 8(12-13) Pages: 2706-2714
• [Journal Article] Participation of both host and virus factors in induction of severe acute respiratory syndrome (SARS) in F344 rats infected with SARS coronavirus. (2006)
  • Author(s): Nagata N, Iwata N, Hasegawa H, Fukushi S, Yokoyama M, Harashima A, Sato Y, Saijo M, Morikawa S, Sata T
  • Journal Title: Journal of Virology 81(4) Pages: 1848-1857