Pathogenesis and Prognosis of Skin Diseases Caused by Host Immune Responses against EB virus Latent Infections

• Project/Area Number: 17390311
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Dermatology
• Research Institution: Okayama University
• Principal Investigator: IWATSUKI Keiji Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Professor (80126797)
• Co-Investigator(Kenkyū-buntansha): TSUJI Kazuhide Okayama University, Hospital, Assistant Professor (30304356) ; YAMAMOTO Takenobu Okayama University, Hospital, Resident (50379799) ; YAMASAKI Osamu Okayama University, Faculty of Medicine, Visiting Research Fellow (90294462)
• Project Period (FY): 2005 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥14,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥990,000); Fiscal Year 2007: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2006: ¥3,300,000 (Direct Cost: ¥3,300,000); Fiscal Year 2005: ¥6,700,000 (Direct Cost: ¥6,700,000)
• Keywords: EB virus / latent infection / reactivation / host immunity / lvmnhoma / hvdroa vacciniforme / HDAC inhibitor / chronic active EBV infection / NK / T細胞 / 宿主免疫応答 / ウイルス発がん / 蚊刺過敏症

Research Abstract

1) The spectrum of EB virus (EBV)-associated NK/T-cell. lymphoproliferative disorders (LPD): We have registered cases with EBV-asscciated LPD as a reviewing center, and clarified the disease spectrum and the prognoses (Arch Dermatol 2006, Eur J Dermatol 2006). We have established a website registration system for cutaneous lymphomas, and began to collect the epidemiological data.
2) Gene expression analysis using a noninvasive diagnostic method: We have established a noninvasive method using crusts for detection of latently infected EBV and cellular gene products (PATENT PCT/JP2006/317851). This method is available for analysis of other herpesvirus infections and cellular gene expression.
3) Evidence for EBV reactivation in the skin legions, and alteration of latency patterns: Patients with severe diseases expressed a reactivation signal (BZLF-1 mRNA) in the skin lesions, while patients with mild diseases did not. In the mild disgase, however, LMP-1 expression levels were increased as compared with those in peripheral blood. 4) Analysis of EBV-infected cell line cells: We performed cytological analysis on the established cell lines. PMA and certain cytokines successfully induced reactivation in EBV-infected.NK/T-cell clones with a latent-infection cycle.
5) Host immune responses: We found that pathogenic significance of host ea, responses against various EBV gene products was essential in the development of the skin lesions.
6) Therapeutic approach: Host immune responses evoked to C/T antigens were analysed (Int J Cancer 2007). Immune ivasion mechanisms were studied in the same model (Cancer Immunol Immunother 2006). We found that some EBV-infected cells were sensitive to HDAC inhibitors. These observations may provide valuable data for immunopharmacological treatments for EBV-related LPD.
7) We have drown out the version of guideline for cutaneous lymphomas including EBV-associaiated LPD.

Research Products

• [Journal Article] Induction of immune response against NY-ESO-1 by CHP-NY-ESO-1 vaccination and immune regulation in a melanoma patient. (2008)
  • Author(s): Tsuji K, Iwatsuki K(15番), et. al.
  • Journal Title: Cancer Immunology and Immunotherapy (印刷中)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Tracing of the molecular remnants of herpesvirus infections in necrotic skin tissue. (2008)
  • Author(s): Yamamoto T, Iwatsuki K(4番), et. al.
  • Journal Title: European Journal of Dermatology (印刷中)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Induction of immune response against NY-ESO-1 by CHP-NY-ESO-1 vaccination and immune regulation in a melanoma patient (2008)
  • Author(s): Tsuji, K., Hamada, T., Uenaka, A., Wada, H., Sato, E., Isobe, M., Asagoe, K., Yamasaki, O., Shiku, H., Ritter, G., Murphy, R., Hoffman, EW., Old, LJ., Nakayama, E., Iwatsuki, K
  • Journal Title: Cancer Immunol Immunother (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Tracing of the molecular remnants of herpesvirus infections in necrotic skin tissue (2008)
  • Author(s): Yamamoto, T., Yamada, A., Tsuji, K., Iwatsuki, K
  • Journal Title: Eur J Dermatol (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A novel, noninvasive diagnostic probe for hydroa vacciniforme and related disorders-Detection of latency-associated Epstein-Barr virus transcripts in the crusts. (2007)
  • Author(s): Yamamoto T, Iwatsuki K(5番), et. al.
  • Journal Title: Journal of Microbiological Methods 68 Pages: 403-407
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Antibody response against NY-ESO-1 in CHP-NY-ESO-1 vaccinated patients. (2007)
  • Author(s): Kawabata R, Iwatsuki K(13番), et. al.
  • Journal Title: International Journal of Cancer 120 Pages: 2178-2184
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] T cell immunomonitoring and tumor responses in patients immunized with a complex of cholesterol-bearing hydrophobized pilluan (CHP) and NY-ESO-1 protein. (2007)
  • Author(s): Uenaka A, Iwatsuki K(13番), et. al.
  • Journal Title: Cancer Immunity 7 Pages: 9-19
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Recovery from Sezary syndrome following Mycobacterium avium spondylitis. (2007)
  • Author(s): Yamada A, Iwatsuki K(7番), et. al.
  • Journal Title: British Journal of Dermatology 157 Pages: 1270-1271
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] A novel, noninvasive diagnostic probe for hydroa vacciniforme and related disorders -Detection of latency-associated Epstein-Barr virus transcripts i n the crusts (2007)
  • Author(s): Yamamoto, T., Tsuji, K., Suzuki, D., Morizane, S., Iwatsuki, K
  • Journal Title: J Microbiol Methods 68 Pages: 403-407
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Antibody response against NY-ESO-1 in CHP-NY-ES0-1 vaccinated patients (2007)
  • Author(s): Kawabata, R., Wada, H., Isobe, M., Saika, T., Sato, S., Uenaka, A., Miyata, H., Yasuda, T., Doki, Y., Noguchi, Y., Kumon, H., Tsuji, K., Iwatsuki, K., Shiku, H., Ritter, G., Murphy, R.,Hoffman, Eric., Old Lloyd, J., Medan, M., Nakayama, E
  • Journal Title: Int J Cancer 120 Pages: 2178-2184
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] T cell immunomonitoring and tumor responses in patients immunized with a complex of cholesterol-bearing hydrophobized pilluan (CHP) and NY-ESO-1 protein (2007)
  • Author(s): Uenaka, A., Wada, H., Isobe, M., Saika, T., Tsuji, K., Sato, E., Sato, S., Noguchi, Y., Kawabata, R., Yasuda, T., Doki, Y., Kumon, H., Iwatsuki, K., Shiku, H., Monden, M., Jungbluth, AA., Ritter, G., Murphy, R., Hoffman, E., Old, LJ., Nakayama, E
  • Journal Title: Cancer Immunity 7 Pages: 9-19
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Recovery from Sezary syndrome following Mycobacterium aviumspondylitis (2007)
  • Author(s): Yamada, A., Yamasaki, O., Asagoe, K., Tsuji, K., Hamada, T., Ota, Y., Iwatsuki, K
  • Journal Title: Br J Dermatol 157 Pages: 1270-1271
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Antibody response against NY-ESO-1 in CHP-NY-ESO-1 vaccinated patients. (2007)
  • Author(s): Kawabata R, et. al.
  • Journal Title: International Journal of Cancer 120 Pages: 2178-2184
  • Peer Reviewed
• [Journal Article] Prospective study of clinical symptoms and skin test reactions in medical students exposed to formaldehyde gas. (2007)
  • Author(s): Takahashi S, et. al.
  • Journal Title: Journal of Dermatology 34 Pages: 283-289
  • Peer Reviewed
• [Journal Article] T cell immunomonitoring and tumor responses in patients immunized with a complex of cholesterol-bearing hydrophobized pullulen (CHP) and NY-ESO-1 protein. (2007)
  • Author(s): Uenaka A, et. al.
  • Journal Title: Cancer Immunity 7 Pages: 9-9
  • Peer Reviewed
• [Journal Article] A novel fusion gene of collagen type I alpha 1 (exon 31) and platelet-derived growth factor B-chain (exon 2) in dermatofibrosarcoma protuberans. (2007)
  • Author(s): Nakanishi G, et. al.
  • Journal Title: European Journal of Dermatology 17 Pages: 217-219
  • Peer Reviewed
• [Journal Article] Infectious complications and managements for surgical site infections in genital Paget's disease. (2007)
  • Author(s): Yamasaki O, et. al.
  • Journal Title: Journal of European Academy of Dermatovenereology 21 Pages: 897-901
  • Peer Reviewed
• [Journal Article] A novel homozygous mutation of the EVER1/TMC6 gene in a Japanese patient with epidermodysplasia verruciformis. (2007)
  • Author(s): Aochi S, et. al.
  • Journal Title: British Journal of Dermatology 157 Pages: 1265-1266
  • Peer Reviewed
• [Journal Article] Recovery from Sezary syndrome following Mycobacterium avium spondylitis. (2007)
  • Author(s): Yamada A, et. al.
  • Journal Title: British Journal of Dermatology 157 Pages: 1270-1271
  • Peer Reviewed
• [Journal Article] Leukocyte common antigen-negative, aggressive cutaneous anaplastic large cell lymphoma with prominent pseudocarcinomatous hyperplasia. (2007)
  • Author(s): Sugiyama H, et. al.
  • Journal Title: European Journal of Dermatology 18 Pages: 74-77
  • Peer Reviewed
• [Journal Article] Induction of immune response against NY-ESO-1 by CHP-NY-ESO-1 vaccination and immune regulation in a melanoma patient. (2007)
  • Author(s): Tuji K, et. al.
  • Journal Title: Cancer Immunology and Immunotherapy E-pub(web掲載)
  • Peer Reviewed
• [Journal Article] A novel,noninvasive diagnostic probe for hyfroa vacciniforme and related disorders : Detection of latency-associated Epstein-Barr virus transcript in the crusts. (2007)
  • Author(s): Yamamoto T, Tsuji K, Iwatsuki K( et al.
  • Journal Title: Journal /of Microbiological Methods 68 Pages: 403-407
• [Journal Article] Pathogenic link between hydroa vacciniforme and Epstein-Barr virus-associated hematological disorders. (2006)
  • Author(s): Iwatsuki K, et. al.
  • Journal Title: Archives of Dermatology 142 Pages: 587-595
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Toward a comprehensive quantitative proteome database-protein expression map of lymphoid neoplasms by 2-D DIGE and MS. (2006)
  • Author(s): Fujii K, Iwatsuki K(7番), et. al.
  • Journal Title: Proteomics 6 Pages: 4856-4876
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Pathogenic link between hydroa vacciniforme and Epstein-Barr virus-associated hematological disorders (2006)
  • Author(s): Iwatsuki, K., Satoh, M., Yamamoto, T., Oono, T., Morizane, S., Ohtsuka, M., Xu Zi-Gang, Suzuki, D., Tuji, K
  • Journal Title: Arch Dermatol 142 Pages: 587-595
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Toward a comprehensive quantitative proteome database-protein expression map of lymphoid neoplasms by 2-D DIGE and MS (2006)
  • Author(s): Fujii, K., Kondo, T., Yamada, M., Iwatsuki, K., Hirohashi, S
  • Journal Title: Proteomics 6 Pages: 4856-4876
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Extranodal NK/T-cell lymphoma, nasal-type (2006)
  • Author(s): Kohler, S., Iwatsuki, K., Jaffe, E.S., Chan, J.K.C
  • Journal Title: World Health Organization Classification of Tumours -Pathology and Genetics of Skin Tumors-, (LeBoit PE, Burg G, Weedon D and Sarasin A eds), IARC Press, Lyon Pages: 191-192
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Nasal NK/T-cell lymphoma preceded by a puffy eyelid and swollen cheek due to intramuscular infiltration of Epstein-Barr virus-infected cells (2006)
  • Author(s): Iwatsuki, K., Ohtsuka, M
  • Journal Title: Cutaneous Lymphomas Unusual Cases 2(Burg G, Kempf W, Michaelis S and Faith J eds), Steinkopff, Darmstadt Pages: 48-49
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Pathogenic link between hydroa vacciniforme and Epstein-Barr virus-associated hematological disorders (2006)
  • Author(s): lwatsuki K, Satoh M, Yamamoto T, Tsuji K( et al.
  • Journal Title: Archives of Dermatology 142 Pages: 587-595
• [Journal Article] Toward a comprehensive quantitative proteome data base : Protein expression map of lymphomatoid neoplasms by 2-D DIGE. and MS. (2006)
  • Author(s): Fujii K, Kondo T, Iwatsuki K( et al.
  • Journal Title: Proteomics 6 Pages: 4856-4876
• [Journal Article] Reactive intravascular histiocytosis associated with tonsillitis (2006)
  • Author(s): Asagoe K, 0fuji R, Iwatsuki K
  • Journal Title: British Journal of Dermatology 153 Pages: 560-563
• [Journal Article] A mutilating arthropathy, Rhupus Hahds'associated with multiple synovial cysts in a patient with systemic lupuss erythematosus (2006)
  • Author(s): Hitomi K, Yamasaki O, Asagoe K, Iwatsuki K( et al.
  • Journal Title: Journal of Dermatology 33 Pages: 415-418
• [Journal Article] Staphylococcal cutaneous infections : invasion,evasion and aggression (2006)
  • Author(s): Iwatsuki K, Yamasaki 0, Morizane S, 〔)ono T
  • Journal Title: Journal of Dermatological Science 42 Pages: 203-214
  • NAID: 10020549417
• [Journal Article] Pathogenic link between hydroa vacciniforme and Epstein-Barr virus-associated hematological disorders. (2006)
  • Author(s): Iwatsuki K et al.
  • Journal Title: Archives of Dermatology (in press)
• [Journal Article] Eradication of Epstein-Barr virus episome and associated inhibition of infected tumor cell growth by adenovirus vector-mediated transduction of dominant-negative EBNA1 (2005)
  • Author(s): Nasimuzzaman M et al.
  • Journal Title: Molecular Therapy 11 Pages: 578-590
• [Journal Article] Mosquito salivary gland extracts induce EBV-infected NK cell oncogenesis via CD4+ T cells in patients with hypersensitivity to mosquito bites (2005)
  • Author(s): Asada H et al.
  • Journal Title: Journal of Investigative Dermatology 125 Pages: 956-961
• [Journal Article] The role of CD4 and CD8 cytotoxic T lymphocytes in the formation of viral vesicles (2005)
  • Author(s): Morizane S et al.
  • Journal Title: British Journal of Dermatology 153 Pages: 981-986
• [Journal Article] Characterization of Epsten-Barr virus-infected natural killer lymphocytes in a patient with hypersensitivity to mosquito bites (2005)
  • Author(s): Yamamoto T et al.
  • Journal Title: Journal of American Academy of Dermatology 53 Pages: 912-914
• [Journal Article] Fatal natural killer cell lymphoma arising in a patient with a crop of Epstein-Bar virus-associated disorders (2005)
  • Author(s): Nitta Y et al.
  • Journal Title: European Journal of Dermatology 15 Pages: 503-506
• [Presentation] Cellular and molecular events leading to cutaneous Epstein-Barr virus-associated T/NK lymphoproliferative disorders. (2008)
  • Author(s): Iwatsuki K
  • Organizer: International Symposium on the Biology and Immunology of Cutaneous Lymphoma
  • Place of Presentation: ベルリン
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Cellular and molecular events leading to cutaneous Epstein-Barr virus-associated T/NK lymphoproliferative disorders (2008)
  • Author(s): Iwatsuki, K
  • Organizer: International Symposium on the Biology and Immunology of Cutaneous Lymphoma Berlin
  • Place of Presentation: Berlin, Germany
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] EBV infection and skin diseases (2007)
  • Author(s): Iwatsuki K
  • Organizer: 21st World Congress of Dermatology
  • Place of Presentation: ブエノスアイレス
  • Year and Date: 2007-10-03
• [Presentation] Virus-related cutaneous lymphomas. (2007)
  • Author(s): Iwatsuki K
  • Organizer: 21st World Congress of Dermatology
  • Place of Presentation: ブエノスアイレス
  • Year and Date: 2007-10-03
• [Presentation] Virus lymphomas (2007)
  • Author(s): Iwatsuki K
  • Organizer: Joint Meeting of the ISCL and EORTC
  • Place of Presentation: ブエノスアイレス
  • Year and Date: 2007-09-29
• [Presentation] Cutaneous lymphomas in Japan (2007)
  • Author(s): Iwatsuki K
  • Organizer: The 15th Korea-Japan Joint Meeting of Dermatology
  • Place of Presentation: 済州島
  • Year and Date: 2007-06-03
• [Presentation] Cutaneous lymphomas in Japan (2007)
  • Author(s): Iwatsuki K
  • Organizer: The 15th Korea-Japan Joint Meeting of Dermatology
  • Place of Presentation: 済州島(韓国)
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Virus-related cutaneous lymphomas (2007)
  • Author(s): Iwatsuki K
  • Organizer: 21st World Congress of Dermatology
  • Place of Presentation: ブエノスアイレス
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Cutaneous lymphoma in Japan (2007)
  • Author(s): Iwatsuki, K
  • Organizer: The 15th Korea-Japan Joint Meeting of Dermatology, Jeju
  • Place of Presentation: Korea
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Virus-related cutaneous lymphomas (2007)
  • Author(s): Iwatsuki, K
  • Organizer: 21st World Congress of Dermatology
  • Place of Presentation: Buenos Aires, Argentina
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] Extranodal NK/T-cell lymphoma, nasal type. Pp191-192(LeBoit PE, Burg G, Weedon D and Sarasin A eds, Tumours-Pathology and Genetics of Skin Tumours (2006)
  • Author(s): Kohler S, lwatsuki K, et. al.
  • Total Pages: 2
  • Publisher: IARC Press, Lyon
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Nasal NK/T-cell lymphoma preceded by a puffy eyelid and swollen cheek due to intra muscular infiltration of Epstein-Barr virus-infected cells.(Burg G, Kempf W, Michaelis S and Feith J eds. Cutaneous Lymphomas Unusual Cases 2 (2006)
  • Author(s): Iwatsuki K, Ohtsuka M
  • Total Pages: 2
  • Publisher: Steinkopff, Darmstadt
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Extranodal NK/t-cell Iymphoma,nasal type. In Pathology and Genetics, Skin Tumours (2006)
  • Author(s): Kohler S, Iwatsuki K( et al.
  • Total Pages: 2
  • Publisher: IARC Press,Lyon
• [Book] Classification Tumours-Pathology and Genetics of Skin Tumours (2005)
  • Author(s): Kohler S et al.
  • Total Pages: 2
  • Publisher: IARC Press, Lyon
• [Remarks]
  • URL: http://www.derma-okayama.net/skin_archive/index_2.html
• [Patent(Industrial Property Rights)] ウイルス潜伏感染の検査方法および検査用キット (2006)
  • Inventor(s): 岩月啓氏, 山本剛伸
  • Industrial Property Rights Holder: 岡山大学
  • Filing Date: 2006-09-08
  • Description: 「研究成果報告書概要(和文)」より
  • Overseas
• [Patent(Industrial Property Rights)] ウイルス潜伏感染の検査方法および検査用キット (2006)
  • Inventor(s): 岩月啓氏, 山本剛伸
  • Industrial Property Rights Holder: 岡山大学
  • Filing Date: 2006-09-08
• [Patent(Industrial Property Rights)] ウイルス潜伏感染の検査方法および検査用キット (2005)
  • Inventor(s): 岩月 啓氏, 山本 剛仲
  • Industrial Property Rights Holder: 国立大学法人岡山大学
  • Filing Date: 2005-09-09