Tokyo Medical and Dental University Graduate School
Department of Immunotherapeutics

Prof. Mari, KANNAGI

Tokyo Medical and Dental University
Graduate School
Department of Immunotherapeutics

1-5-45, Yushima, Bunkyo-ku
Tokyo 113-8519, Japan
Telephone: +81-3-5803-5798
Facsimili: +81-3-5803-0235

Laboratory Members
Mari, Kannagi
Associate Professor Takao, Masuda
Assistant Professor Atsuhiko, HASEGAWA
Assistant Professor Yoshiko, NAGANO
Part-time instructor
Sayaka, ITO
Postdoctoral Fellow
Graduate School Student Satomi, ANDO


Yuji, Murakami


Riho, KOGA
Emiko, OKAWA


Viral infection causes various diseases including immunodeficiency, malignancy, autoimmunity, and inflammation. Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS), Human T-cell leukemia virus type-I (HTLV-I) causes adult T-cell leukemia (ATL) and various chronic inflammatory autoimmune-like diseases, and severe acute respiratory syndrome corona virus (SARS-CoV) causes SARS resembling acute respiratory distress syndrome. To understand mechanisms of these diseases, investigation on host immune is indispensable. Immune responses are usually protective but sometimes harmful for the host, and are important determinants for disease manifestation. The goal of research in our department is elucidation of the role of host immunity in the diseases and development of effective immunotherapy. We also investigate intracellular mechanisms of viral replication to target direct molecules for therapy. Our research area is in between clinical and basic science, involving immunolgy, microbiology, and molecular biology.

Resarch Subjects

1. Analysis of immunological risks for ATL development in HTLV-I-carriers.
2. Development of anti-tumor vaccine using experimental animal model system for ATL.
3. Immunological and molecular mechanism of HTLV-1 induced tumorgenesis.
4. Molecular mechanism of HIV replication especially related to HIV-1 integrase.
5. Experiments based on gene therapy to suppress HIV-1 replication.
6. Immunological suppressive mechanisms on HIV-1 replication.
7. Molecular mechanisms of SARS-CoV-induced fatal inflammatory responses.

Recent achievement

1. Induction of anti-tumor immunity by DNA- or peptide vaccine targeting Tax in a rat model of ATL.
2. Identification of major epitopes of Tax-specific CTL restricted by HLA-A2, A24, and A11.
3. Detection of strong Tax-specific CTL reactivation in ATL patients following hematopoietic stem cell transplantation.
4. Induction of HTLV-I-specific immune tolerance and elevated proviral loads by oral HTLV-I infection in rats.
5. Reduction of HTLV-I proviral load in asymptomatic HTLV-I-carrying rats by re-immunization.
6. Establishment of a detection system for Tax-specific T-cell response.

1. Demonstration of the essential roles of HIV-1 integrase in multiple steps of the virus replication.
2. Identification of a HIV-1 integrase-binding host factor, Gemin2, which is essential for HIV-1 replication.
3. Identification of critical amino acid residues in HIV-1 integrase required for efficient proviral DNA formation.
4. Identification of shRNA sequences in HIV-1 integrase, highly efficient for suppression of HIV-1 replication.
5. Detection of MHC-irrelevant anti-HIV-1 activities in CD8+ CTL.
6. Demonstration of ICOS-mediated HIV-1-resistance in CD4+ T cells.

1. Demonstration of strong NF-kappa B-activation and inflammatory chemokine-induction by SARS-CoV accessory proteins 3a/X1 and 7a/X4.



[54] Suehiro Y, Hasegawa A, Iino T, Sasada A, Watanabe N, Matsuoka M, Takamori A, Tanosaki R, Utsunomiya A, Choi I, Fukuda T, Miura O, Takaishi S, Teshima T, Akashi K, Kannagi M, Uike N, Okamura J. Clinical outcomes of a novel therapeutic vaccine with Tax peptide-pulsed dendritic cells for adult T cell leukaemia/lymphoma in a pilot study. Br J Haematol. 169(3):356-67, 2015

[53] Kinpara S, Ito S, Takahata T, Saitoh Y, Hasegawa A, Kijiyama M, Utsunomiya A, Masuda M, Miyazaki Y, Matsuoka M, Nakamura M, Yamaoka S, Masuda T, Kannagi M. Involvement of double-stranded RNA-dependent protein kinase and antisense viral RNA in the constitutive NFƒÈB activation in adult T-cell leukemia/lymphoma cells. Leukemia., in press.


[52] Araya N, Sato T, Ando H, Tomaru U, Yoshida M, Coler-Reilly A, Yagishita N, Yamauchi J, Hasegawa A, Kannagi M, Hasegawa Y, Takahashi K, Kunitomo Y, Tanaka Y, Nakajima T, Nishioka K, Utsunomiya A, Jacobson S, Yamano Y. HTLV-1 induces a Th1-like state in CD4+CCR4+ T cells. J Clin Invest. 124(8):3431-42, 2014

[51] Tanaka Y, Takahashi Y, Tanaka R, Kodama A, Fujii H, Hasegawa A, Kannagi M, Ansari AA, Saito M. Elimination of human T cell leukemia virus type-1-infected cells by neutralizing and antibody-dependent cellular cytotoxicity-inducing antibodies against human t cell leukemia virus type-1 envelope gp46. AIDS Res Hum Retroviruses. 30(6):542-52, 2014


[50] S. Kinpara, M. Kijiyama, A. Takamori, A. Hasegawa, A. Sasada, T. Masuda, Y.
Tanaka, A. Utsunomiya and M. Kannagi. Interferon-ƒ¿ (IFN-ƒ¿) suppresses HTLV-1 gene expression and cell cycling, while IFN-ƒ¿ combined with zidovudin induces p53 signaling and apoptosis in HTLV-1-infected cells.
Retrovirology. 10: 52, 2013.

[49] Tamai, Y., A. Hasegawa, A. Takamori, A. Sasada, R. Tanosaki, I. Choi, A. Utsunomiya, Y. Maeda, Y. Yamano, T. Eto, K. R. Koh, H. Nakamae, Y. Suehiro, K. Kato, S. Takemoto, J. Okamura, N. Uike, and M. Kannagi.
Potential Contribution of a Novel Tax Epitope-Specific CD4+ T Cells to Graft-versus-Tax Effect in Adult T Cell Leukemia Patients after Allogeneic Hematopoietic Stem Cell Transplantation.
J Immunol. 190(8): 4382-92. 2013


[48] Kannagi, M., A. Hasegawa, A. Takamori, S. Kinpara, and A. Utsunomiya.
The roles of acquired and innate immunity in human T-cell leukemia virus type 1-mediated diseases.
Front Microbiol 3:323.


[47] Masuda, T. Non-Enzymatic Functions of Retroviral Integrase: The Next Targetfor Novel Anti-HIV Drug Development.
Frontiers Microbiol. 2, 210. 2011

Takamori A, Hasegawa A, Utsunomiya A, Maeda Y, Yamano Y, Masuda M, Shimizu Y, Tamai Y, Sasada A, Zeng N, Choi I, Uike N, Okamura J, Watanabe T, Masuda T, Kannagi M.
Functional impairment of Tax-specific but not cytomegalovirus-specific CD8+ T lymphocytes in a minor population of asymptomatic human T-cell leukemia virus type 1-carriers.
Retrovirology. 8: 100.

[45] Kannagi M, Hasegawa A, Kinpara S, Shimizu Y, Takamori A, Utsunomiya A.
Double control systems for human T-cell leukemia virus type 1 by innate and acquired immunity.
Cancer Sci., 102(4):670-6.


[44] Ahmed N, Hayashi T, Hasegawa A, Furukawa H, Okamura N, Chida T, Masuda T, Kannagi M.
Suppression of human immunodeficiency virus type 1 replication in macrophages by commensal bacteria preferentially stimulating Toll-like receptor 4.
J Gen Virol., 91(Pt 11):2804-13.

[43] Hayashi T, Nishitsuji H, Takamori A, Hasegawa A, Masuda T, Kannagi M.
DNA-dependent activator of IFN-regulatory factors enhances the transcription of HIV-1 through NF-ƒÈB.
Microbes Infect., 12(12-13):937-47.


[42] Nishitsuji H, Hayashi T, Takahashi T, Miyano M, Kannagi M, Masuda T.
Augmentation of reverse transcription by integrase through an interaction with host factor, SIP1/Gemin2 Is critical for HIV-1 infection.
PLoS One.

[41] N.Takatsuka, A. Hasegawa, A. Takamori, Y. Shimizu, H. Kato, T. Ohashi, T. Amagasa, T. Masuda, M. Kannagi.
Induction of IL-10- and IFN-g-producing T-cell responses by autoreactive T-cells expressing human T-cell leukemia virus type I Tax.
Int. Immunol., 21(9):1089-100.

[40] S. Obitsu, N. Ahmed, H. Nishitsuji, A. Hasegawa, K. Nakahama, I. Morita, K. Nishigaki, T. Hayashi, T. Masuda, M. Kannagi.
Potential enhancement of osteoclastogenesis by severe acute respiratory syndrome coronavirus 3a/X1 protein.
Arch. Virol., 154(9):1457-64.

[39] S. Kinpara, A. Hasegawa, A. Utsunomiya, H. Nishitsuji, H. Furukawa, T. Masuda, and M. Kannagi.
Stromal cell-mediated suppression of human T-cell leukemia virus type-1 expression in vitro and in vivo through type-I interferon.
J. Virol. 83: 5101-5108.

[38] Y. Shimizu, A. Takamori, A. Utsunomiya, M. Kurimura, Y.Yamano, M. Hishizawa, A. Hasegawa, F. Kondo, K. Kurihara, N. Harashima, T. Watanabe, J. Okamura, T. Masuda, and M. Kannagi.
Impaired Tax-specific T-cell responses with insufficient control of HTLV-1 in a subgroup of individuals at asymptomatic and smoldering stages.
Cancer Sci., 100: 481-489.


[37] M. Washiyma, K. Nishigaki, N. Ahmed, S. Kinpara, Y. Ishii, N. Kanzawa, T. Masuda, and M. Kannagi.
IL-2 withdrawal induces HTLV-1 expression through p38 activation in ATL cell lines.
FEBS Letters, 581: 5207-5212.

[36] Mari Kannagi.
Immunologic control of HTLV-I and Adult T-cell Leukemia.
Int. J. Hematol. 86: 113-117.


[35] Kanzawa N, Nishigaki K, Hayashi T, Ishii Y, Furukawa S, Niiro A, Yasui F, Kohara M, Morita K, Matsushima K, Le MQ, Masuda T, Kannagi M.
Augmentation of chemokine production by severe acute respiratory syndrome coronavirus 3a/X1 and 7a/X4 proteins through NF-kappaB activation.
FEBS Lett., 580(30):6807-12.

[34] Nishitsuji H, Kohara M, Kannagi M, Masuda T.
Effective suppression of human immunodeficiency virus type 1 through a combination of short- or long-hairpin RNAs targeting essential sequences for retroviral integration.
J Virol., 80(15):7658-66.

[33] Komori K, Hasegawa A, Kurihara K, Honda T, Yokozeki H, Masuda T, Kannagi M.
Reduction of human T-cell leukemia virus type 1 (HTLV-1) proviral loads in rats orally infected with HTLV-1 by reimmunization with HTLV-1-infected cells.
J Virol., 80(15):7375-81.

[32] Hamamoto S, Nishitsuji H, Amagasa T, Kannagi M, Masuda T.
Identification of a novel human immunodeficiency virus type 1 integrase interactor, Gemin2, that facilitates efficient viral cDNA synthesis in vivo.
J Virol., 80(12):5670-7.

[31] Kurihara K, Shimizu Y, Takamori A, Harashima N, Noji M, Masuda T, Utsunomiya A, Okamura J, Kannagi M.
Human T-cell leukemia virus type-I (HTLV-I)-specific T-cell responses detected using three-divided glutathione-S-transferase (GST)-Tax fusion proteins.
J Immunol Methods., 313(1-2):61-73.

[30] Kubo M, Nishitsuji H, Kurihara K, Hayashi T, Masuda T, Kannagi M.
Suppression of human immunodeficiency virus type 1 replication by arginine deiminase of Mycoplasma arginini.
J Gen Virol., 87(Pt 6):1589-93.


[29] Harashima N, Tanosaki R, Shimizu Y, Kurihara K, Masuda T, Okamura J, Kannagi M.
Identification of two new HLA-A*1101-restricted tax epitopes recognized by cytotoxic T lymphocytes in an adult T-cell leukemia patient after hematopoietic stem cell transplantation.
J Virol., 79(15):10088-92.2005.

[28] Kannagi M, Harashima N, Kurihara K, Ohashi T, Utsunomiya A, Tanosaki R, Masuda M, Tomonaga M, Okamura J.
Tumor immunity against adult T-cell leukemia.
Cancer Sci., 96(5):249-55.2005.

[27] Kurihara K, Harashima N, Hanabuchi S, Masuda M, Utsunomiya A, Tanosaki R, Tomonaga M, Ohashi T, Hasegawa A, Masuda T, Okamura J, Tanaka Y, Kannagi M.
Potential immunogenicity of adult T cell leukemia cells in vivo.
Int J Cancer., 114(2):257-67.2005.


[26] Ikeda T, Nishitsuji H, Zhou X, Nara N, Ohashi T, Kannagi M, Masuda T.
Evaluation of the functional involvement of human immunodeficiency virus type 1 integrase in nuclear import of viral cDNA during acute infection.
J Virol., 78(21):11563-73.2004.

[25] Emori Y, Ikeda T, Ohashi T, Masuda T, Kurimoto T, Takei M, Kannagi M.
Inhibition of human immunodeficiency virus type 1 replication by Z-100, an immunomodulator extracted from human-type tubercle bacilli, in macrophages.
J Gen Virol., 85(Pt 9):2603-13, 2004.

[24] Zhou X, Kubo M, Nishitsuji H, Kurihara K, Ikeda T, Ohashi T, Azuma M, Masuda T, Kannagi M.
Inducible-costimulator-mediated suppression of human immunodeficiency virus type 1 replication in CD4+ T lymphocytes.
Virology., 325(2):252-63, 2004.

[23] Kannagi M, Ohashi T, Harashima N, Hanabuchi S, Hasegawa A.
Immunological risks of adult T-cell leukemia at primary HTLV-I infection.
Trends Microbiol., 12(7):346-52, 2004.

[22] Kannagi M, Harashima N, Kurihara K, Utsunomiya A, Tanosaki R, Masuda M.
Adult T-cell leukemia: future prophylaxis and immunotherapy.
Expert Rev Anticancer Ther., 4(3):369-76, 2004.

[21] Nomura M, Ohashi T, Nishikawa K, Nishitsuji H, Kurihara K, Hasegawa A, Furuta RA, Fujisawa J, Tanaka Y, Hanabuchi S, Harashima N, Masuda T, Kannagi M.
Repression of tax expression is associated both with resistance of human T-cell leukemia virus type 1-infected T cells to killing by tax-specific cytotoxic T lymphocytes and with impaired tumorigenicity in a rat model.
J Virol., 78(8):3827-36, 2004.

[20] Nishitsuji H, Ikeda T, Miyoshi H, Ohashi T, Kannagi M, Masuda T.
Expression of small hairpin RNA by lentivirus-based vector confers efficient and stable gene-suppression of HIV-1 on human cells including primary non-dividing cells.
Microbes Infect., 6(1):76-85, 2004.

[19] Harashima N, Kurihara K, Utsunomiya A, Tanosaki R, Hanabuchi S, Masuda M, Ohashi T, Fukui F, Hasegawa A, Masuda T, Takaue Y, Okamura J, Kannagi M.
Graft-versus-Tax response in adult T-cell leukemia patients after hematopoietic stem cell transplantation.
Cancer Res., ;64(1):391-9, 2004.


[18] Liu H, Ohashi T, Masuda T, Zhou X, Kubo M, Kannagi M.
Suppression of HIV-1 replication by HIV-1-irrelevant CD8+ cytotoxic T lymphocytes resulting in preservation of persistently HIV-1-infected cells in vitro.
Viral Immunol., 16(3):381-93, 2003.

[17] Hasegawa A, Ohashi T, Hanabuchi S, Kato H, Takemura F, Masuda T, Kannagi M.
Expansion of Human T-Cell Leukemia Virus Type 1 (HTLV-1) Reservoir in Orally Infected Rats: Inverse Correlation with HTLV-1-Specific Cellular Immune Response.
J Virol.,77:2956-63, 2003.


[16] Ohashi T, Hanabuchi S, Suzuki R, Kato H, Masuda T, Kannagi M.
Correlation of major histocompatibility complex class I downregulation with resistance of human T-cell leukemia virus type 1-infected T cells to cytotoxic T-lymphocyte killing in a rat model.
J Virol.,76:7010-7019, 2002.


[15] Hanabuchi S, Ohashi T, Koya Y, Kato H, Hasegawa A, Takemura F, Masuda T, Kannagi M.
Regression of human T-cell leukemia virus type I (HTLV-I)-associated lymphomas in a rat model: peptide-induced T-cell immunity.
J Natl Cancer Inst.,93:1775-83, 2001.


[14] Kannagi M, Ohashi T, Hanabuchi S, Kato H, Koya Y, Hasegawa A, Masuda T, Yoshiki T.
Immunological aspects of rat models of HTLV type 1-infected T lymphoproliferative disease.
AIDS Res Hum Retroviruses,16:1737-40, 2000.

[13] T. Ohashi, S. Hanabuchi, H. Kato, H. Tateno, F. Takemura, T. Tsukahara, Y. Koya, A. Hasegawa, T. Masuda, and M. Kannagi.
Prevention of Adult T cell leukemia-like lymphoproliferative disease in rats by adoptively transferred T cells from a donor immunized with HTLV-I Tax-coding DNA vaccine.
J. Virol.,74:9610-9616, 2000.

[12] S. Hanabuchi, T. Ohashi, Y. Koya, H. Kato, F. Takemura, K. Hirokawa, T. Yoshiki, H. Yagita, K. Okumura, and M. Kannagi.
Development of human T cell leukemia virus type I (HTLV-I)-transformed tumor in rats following suppression of T cell immunity by CD80 and CD86 blockade.
J. Virol.,74: 428-435, 2000.

[11] N. Tsurutani, M. Kubo, Y. Maeda, N. Yamamoto, M. Kannagi, and T. Masuda.
Identification of critical amino acid residues in IN required for efficient proviral DNA formation at steps prior to integration in dividing and non-dividing cells.
J. Virol.,74: 4795-4806, 2000.


[10] T. Ohashi, S. Hanabuchi, H. Kato, Y. Koya, F. Takemura, K. Hirokawa, T. Yoshiki, Y. Tanaka, M. Fujii, and M. Kannagi.
Induction of ATL-like lymphproliferative disease and its inhibition by adoptive immunotherapy in T-cell deficient nude rats inoculated with syngenic HTLV-I-immortalized cells.
J. Virol.,73: 6031-6040, 1999.

[9] Y. Koya, T. Ohashi, H. Kato, S. Hanabuchi, T. Tsukahara, F. Takemura, K. Etoh, M. Matsuoka, M. Fujii, and M. Kannagi.
Establishment of a seronegative HTLV-I-carrier state in rats inoculated with a syngeneic HTLV-I-immortalized T cell line preferentially expressing Tax.
J. Virol.,73: 6436-6443, 1999.

[8] T. Tsukahara, M. Kannagi, T. Ohashi, H. Kato, M. Arai, G. Nunez, Y. Iwanaga, N. Yamamoto, K. Ohtani, M. Nakamura, and M. Fujii.
Induction of Bcl-xL expression by HTLV-I Tax through NF-kB in apoptosis-resistant T-cell transfectants with Tax.
J. Virol.,73: 7981-7987, 1999.

[7] T. Ohashi, M. Kubo, H. Kato, A. Iwamoto, H. Takahashi, M. Fujii, and M. Kannagi.
Role of class I major histcompatibility complex-restricted and -unrestricted suppression of human immunodeficiency virus type 1 (HIV-1) replication by CD8+ T lymphocytes
J. Gen. Virol.,80: 209-216, 1999.


[6] T. Ohashi, M. Arai, H. Kato, M. Kubo, M. Fujii, N. Yamamoto, A. Iwamoto, M. Kannagi.
High SDF-1 expression in HIV-1 carriers does not correlate with CD8+ T cell-mediated suppression of viral replication.
Virology, 244: 467-472, 1998.

[5] H. Kato, Y. Koya, T. Ohashi, S. Hanabuchi, F. Takemura, M. Fujii, H. Tsujimoto, A. Hasegawa, and M Kannagi.
Oral administration of HTLV-I induces immune unresponsivenesswith persistent infection in adult rats.
J. Virol., 72. 7289-7293, 1998.

[4] M. Arai, T. Ohashi, T. Tsukahara, T. Murakami, T Hori, T. Uchiyama, N. Yamamoto, M. Kannagi, M. Fujii.
Human T cell leukemia virus type 1 Tax protein induces the expression of lymphocyte chemoattractant SDF-1/PBSF.
Virology, 241: 298-303, 1998.


[3] M. Kubo, Ohashi T., Fujii M., Oka S., Iwamoto S., Harada S., and Kannagi M.
Abrogation ofin vitro suppression of HIV-1 replication mediated by CD8+ T lymphocytes of asymptomatic HIV-1 carrers by staphylococcal enterotoxin B and phorbol esters hrough induction of TNF-a.
J. Virol.,71: 7560-7566, 1997.

[2] S. Kishi, Saijo S., Arai M., Karasawa S., Ueda S., Kannagi M., Iwakura Y., Fujii M., and Yonehara S.
Resistance to Fas-mediated apoptosis of peripheral T cells in human T lymphocyte virus type I (HTLV-I) transgenic mice with autoimmune arthropathy.
J. Exp. Med.,186: 57-64, 1997.

[1] Arai, M., Kannagi, M., Matsuoka, M., Sato, T., Yamamoto, N., Fujii, M.
Expression of FAP-1(Fas-associated phosphatase) and resistance to Fas-mediated apoptosis in T-cell lines derived from human T-cell leukemia virus type 1 associated myelopathy/tropical spastic paraparesis.
AIDS Res.Hum.Retroviruses, 14: 261-267, 1997.

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