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南九州ではHTLV-1というウイルスで起こるHTLV-1関連脊髄症（HAM）と成人T細胞白血病（ATL)が多発しています。HAMは1986年に鹿児島大学で発見された脊髄の炎症性疾患であり、患者さんは歩行障害や排尿障害で苦しんでおられます。現在まで種々の治療法が試みられていますが、未だ根治療法がない状態です。
私たちの研究分野は、主にHAMの病態解明とそれを通した新規治療法の開発を目的に研究を行っています。

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主な研究実績

久保田龍二

1. Kodama D, Tanaka M, Matsuzaki T, Nozuma S, Matsuura E, Takashima H, Izumo S, Kubota R. Anti-human T-cell leukemia virus type 1 (HTLV-1) antibody assays in cerebrospinal fluid for the diagnosis of HTLV-1-associated myelopathy/tropical spastic paraparesis. J Clin Microbiol. 59(5): e03230-20, 2021.
2. Kodama D, Tanaka M, Matsuzaki T, Izumo K, Nakano N, Matsuura E, Saito M, Nagai M, Horiuchi M, Utsunomiya A, Takashima H, Kubota R, Izumo S. Inhibition of ABL1 tyrosine kinase reduces HTLV-1 proviral loads in peripheral blood mononuclear cells from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis. PLoS Negl Trop Dis. 2020 14(7): e0008361, 2020.
3. Matsuura E, Kubota R, Tanaka Y, Takashima H, Izumo S. Visualization of HTLV-1-specific cytotoxic T lymphocytes in the spinal cords of patients with HTLV-1-associated myelopathy/tropical spastic paraparesis. J Neuropath Exp Neurol. 74(1): 2-14, 2015.
4. Kawabata T, Higashimoto I, Takashima H, Izumo S, Kubota R. Human T-lymphotropic virus type I (HTLV-I)-specific CD8+ cells accumulate in the lungs of patients infected with HTLV-I with pulmonary involvement. J Med Virol. 84(7): 1120-1127, 2012.
5. Abdullah NH, Abdullah HM, Matsuzaki T, Hayashi D, Tanaka Y, Takashima H, Izumo S, Kubota R. Reduced Tim-3 expression on HTLV-I Tax-specific cytotoxic T lymphocytes in HTLV-I infection. J Infect Dis. 203(7): 948-959, 2011.
6. Kubota R, Hanada K, Furukawa Y, Arimura K, Osame M, Gojobori T, Izumo S. Genetic stability of human T lymphotropic virus type I despite antiviral pressures by CTLs. J Immunol. 178(9), 5966-5972, 2007.
7. Kubota R, Furukawa Y, Izumo S, Usuku K, Osame M. Degenerate specificity of HTLV-I-specific CD8+ T cells during viral replication in patients with HTLV-I-associated myelopathy (HAM/TSP). Blood 101(8): 3074-3081, 2003.
8. Kubota R, Soldan SS, Martin R, Jacobson S. An altered peptide ligand antagonizes antigen-specific T cells of patients with human T lymphotropic virus type I-associated neurological disease. J Immunol. 164: 5192-5198, 2000.
9. Kubota R, Kawanishi T, Matsubara H, Manns A, Jacobson S. Demonstration of human T lymphotropic virus type I (HTLV-I) tax-specific CD8+ cells directly in peripheral blood of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients by intracellular cytokine detection. J Immunol. 161: 482-488, 1998.
10. Greten TF, Slansky JE, Kubota R, Soldan SS, Jaffee EM, Leist TP, Pardoll DM, Jacobson S, Schneck JP. Direct visualization of antigen-specific T lymphocytes: HTLV-I Tax11-19 specific CD8+ T cells are activated in peripheral blood and accumulate in cerebrospinal fluid from HAM/TSP patients. Proc Natl Acad Sci USA. 95: 7568-7573, 1998.
11. Biddison WE, Kubota R, Kawanishi T, Taub DD, Cruikshank WW, Center DM, Connor EW, Utz U, Jacobson S. Human T cell leukemia virus type I (HTLV-I)-specific CD8+ CTL clones from patients with HTLV-I-associated neurologic disease secrete proinflammatory cytokines, chemokines, and matrix metalloproteinase. J Immunol. 159: 2018-2025, 1997.
12. Kubota R, Umehara F, Izumo S, Ijichi S, Matsumuro K, Yashiki S, Fujiyoshi T, Sonoda S, Osame M. HTLV-I proviral DNA amount correlates with infiltrating CD4+ lymphocytes in the spinal cord from patients with HTLV-I-associated myelopathy. J Neuroimmunol. 53: 23-29, 1994.

田中正和

1. Takenouchi N, Tanaka M, Sato T, Yao J, Fujisawa J, Izumo S, Kubota R, Matsuura E. Expression of TSLC1 in patients with HAM/TSP. J NeuroVirology. 26: 404-414, 2020.
2. Tanaka M, Kawazu Y, Yoshida T, Konishi T, Takenouchi N, Miwa M. Effects of radiation based on whole-body irradiation in HTLV-1-infected mice. J Radiat Res. 60: 710-713, 2019.
3. Yao J, Tanaka M, Takenouchi N, Ren Y, Lee SI, Fujisawa JI. Induction of APOBEC3B cytidine deaminase in HTLV-1-infected humanized mice. Exp Ther Med. 17: 3701-3708, 2019.
4. Tanaka M, Tanaka K, Ida C, Oue A, Yamashita S, Yao J, Takenouchi N, Miwa M. Conflicting effects of poly(ADP-ribose)polymerase inhibitor on cell-mediated and virion-mediated HTLV-1 infection. Virus Res. 270: 197653, 2019.
5. Yamashita S, Tanaka M, Nodono H, Hamada A, Hamada T, Hasegawa M, Nishi Y, Moss J, Miwa M. Human alcohol dehydrogenase 1 is an acceptor protein for polyADP-ribosylation. Biochem Pharmacol. 167: 27-32, 2019.
6. Yamashita S, Tanaka M, Sato T, Ida C, Ohta N, Hamada T, Uetsuki T, Nishi Y, Moss J, Miwa M. Effect of mild temperature shift on poly(ADP-ribose) and γH2AX levels in cultured cells. Biochem.Biophys.Res.Commun. 476: 594-599, 2016.
7. Tezuka K, Xun R, Tei M, Ueno T, Tanaka M, Takenouchi N, Fujisawa JI. An animal model of adult T-cell leulemia: humanized mice with HTLV-1-specific immunity. Blood. 123: 346-355, 2014.
8. Tanaka M, Sun B, Tezuka K, Fujisawa JI, Tanaka Y, Hoshino H, Miwa M. Neuraminidase enhances the initial steps of human T-cell leukemia virus type 1 replication. Microbes Infect. 12: 119-125, 2010.
9. Tanaka M, Nitta T, Yoshida T, Konishi T, Kawazu Y, Fujisawa JI, Miwa M. Clonal proliferation of HTLV-1-infected cells is associated with spontaneous malignant tumor formation in mice. Int J Oncol. 35: 701-707, 2009.
10. Nitta T, Tanaka M, Sun B, Sugihara E, Kimura M, Kamada Y, Takahashi H, Hanai S, Jiang S, Fujisawa JI, Miwa M. Reduction of human T-cell leukemia virus type-1 infection in mice lacking nuclear factor-kappaB-inducing kinase. Cancer Sci. 99: 872-878, 2008.
11.  Tanaka M, Ueno T, Nakahara T, Sasaki K, Ishimoto A, Sakai H. Downregulation of CD4 is required for maintenance of viral infectivity of HIV-1. Virology. 311: 316-325, 2003.
12. Tanaka M, Sun B, Fang J, Nitta T, Yoshida T, Kohtoh S, Kikukawa H, Hanai S, Uchida K, Miwa M. Human T-cell leukemia virus type 1 (HTLV-1) infection of mice: proliferation of cell clones with integrated HTLV-1 provirus in lymphoid organs. J Virol. 75: 4420-4423, 2001.

兒玉大介

1.  Kodama D, Tanaka M, Matsuzaki T, Nozuma S, Matsuura E, Takashima H, Izumo S, Kubota R: Anti-Human T-Cell Leukemia Virus Type 1 (HTLV-1) Antibody Assays in Cerebrospinal Fluid for the Diagnosis of HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis. J Clin Microbiol. 59(5):e03230-20, 2021.
2.  Kodama D, Tanaka M, Matsuzaki T, Izumo K, Nakano N, Matsuura E, Saito M, Nagai M, Horiuchi M, Utsunomiya A, Takashima H, Kubota R, Izumo S: Inhibition of ABL1 tyrosine kinase reduces HTLV-1 proviral loads in peripheral blood mononuclear cells from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis. PLoS Negl Trop Dis. 14(7): e0008361, 2020.
3.  Nozuma S, Matsuura E, Kodama D, Tashiro Y, Matsuzaki T, Kubota R, Izumo S, Takashima H: Effects of host restriction factors and the HTLV-1 subtype on susceptibility to HTLV-1-associated myelopathy/tropical spastic paraparesis. Retrovirology 14(1):26, 2017.
4. Kodama D, Saito M, Matsumoto W, Sabouri AH, Izumo S, Arimura K, Usuku K, Bangham CRM, Osame M: Longer dinucleotide repeat polymorphism in matrix metalloproteinase-9 (MMP-9) gene promoter which correlates with higher HTLV-I Tax mediated transcriptional activity influences the risk of HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). J Neuroimmunol 156(1-2):188-94, 2004.
5. Umehara F, Yamaguchi N, Kodama D, Takenaga S, Kiwaki T, Sonoda Y, Arimura Y, Yamada H, Arimura K, Osame M: Polyneuropathy with minifascicle formation in a patient with 46XY mixed gonadal dysgenesis. Acta Neuropathol 98(3): 309-12, 1999.

有島志保

1. Xing HQ, Zhang Y, Izumo K, Arishima S, Kubota R, Ye X, Xu Q, Mori K, Izumo S.Decrease of aquaporin-4 and excitatory amino acid transporter-2 indicate astrocyte dysfunction for pathogenesis of cortical degeneration in HIV-associated neurocognitive disorders.
   Neuropathology. 2017 Feb;37(1):25-34.
2. Sakiyama Y, Kanda N, Higuchi Y, Yoshimura M, Wakaguri H, Takata Y, Watanabe O, Yuan J, Tashiro Y, Saigo R, Nozuma S, Yoshimura A, Arishima S, Ikeda K, Shinohara K, Arata H, Michizono K, Higashi K, Hashiguchi A, Okamoto Y, Hirano R, Shiraishi T, Matsuura E, Okubo R, Higuchi I, Goto M, Hirano H, Sano A, Iwasaki T, Matsuda F, Izumo S, Takashima H.New type of encephalomyelitis responsive to trimethoprim/sulfamethoxazole treatment in Japan.Neurol Neuroimmunol Neuroinflamm. 2015 Aug 13;2(5)
3. Saito M, Tanaka R, Arishima S, Matsuzaki T, Ishihara S, Tokashiki T, Ohya Y, Takashima H, Umehara F, Izumo S, Tanaka Y.Increased expression of OX40 is associated with progressive disease in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis.Retrovirology. 2013 May 7;10:51.

主な研究費取得状況

久保田龍二

 田中正和

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