Study on HHV6 reactivation mechanism in DIHS focusing on virus-derived chemokine receptor

• Project/Area Number: 26461699
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Dermatology
• Research Institution: Nara Medical University
• Principal Investigator: ASADA HIDEO 奈良県立医科大学, 医学部, 教授 (60252681)
• Co-Investigator(Kenkyū-buntansha): 宮川 史 奈良県立医科大学, 医学部, 講師 (00346024)
• Co-Investigator(Renkei-kenkyūsha): MORI YASUKO 神戸大学, 医学部, 教授 (50343257)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 薬剤性過敏症症候群 / DIHS / HHV-6 / ヒトヘルペスウイルス / 再活性化 / TARC / ケモカイン / CD134 / ウイルスレセプター / MDC

Outline of Final Research Achievements

HHV-6 reactivation is involved in the pathogenesis of drug-induced hypersensitivity syndrome (DIHS), but the reactivation mechanism is still unclear. In this study, we aimed to elucidate the mechanism of HHV-6 reactivation focusing on the marked elevation of Th2-related chemokine (TARC) in the acute phase of DIHS and the fact that HHV-6 has TARC receptor.
As a result, we found that HHV-6 receptor (CD134) markedly increased on the T cell surface correlated with the elevation of serum TARC level in the acute phase of DIHS, and that blood HHV-6 DNA amount was also correlated with serum TARC level. These findings suggested that increased expression of CD134 associated with elevated TARC might be involved in HHV-6 reactivation in vivo.

Research Products

• [Journal Article] Novel interferon-γ enzyme-linked immunoSpot assay using activated cells for identifying hypersensitivity-inducing drug culprits. (2017)
  • Author(s): Kato K, Kawase A, Azukizawa H, Hanafusa T, Nakagawa Y, Murota H, Sakaguchi S, Asada H, Katayama I
  • Journal Title: J Dermatol Sci Volume: 86 Issue: 3 Pages: 222-229
  • DOI: 10.1016/j.jdermsci.2017.03.007
  • Peer Reviewed / Open Access
• [Journal Article] EGFR inhibitory monoclonal antibodies and EGFR tyrosine kinase inhibitors have distinct effects on the keratinocyte innate immune response. (2017)
  • Author(s): Ommori R, Park K, Miyagawa F, Azukizawa H, Kanno M, Asada H.
  • Journal Title: Br J Dermatol Volume: - Issue: 3 Pages: 796-797
  • DOI: 10.1111/bjd.15445
  • Peer Reviewed / Open Access
• [Journal Article] Preferential expression of CD134, an HHV-6 cellular receptor, on CD4 T cells in drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS). (2016)
  • Author(s): Miyagawa F, Nakamura Y, Miyashita K, Iioka H, Himuro Y, Ogawa K, Nishimura C, Nishikawa M, Mitsui Y, Ito Y, Ommori Rie, Mori Y, Asada H
  • Journal Title: J Dermatol Sci Volume: 83 Issue: 2 Pages: 151-154
  • DOI: 10.1016/j.jdermsci.2016.05.001
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Essential requirement for IFN regulatory factor 7 in autoantibody production but not development of nephritis in Murine Lupus. (2016)
  • Author(s): Miyagawa F, Tagaya Y, Ozato K, Asada H
  • Journal Title: J Immunol Volume: 197 Issue: 6 Pages: 2167-2176
  • DOI: 10.4049/jimmunol.1502445
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical and immunologic features of recurrent herpes zoster (HZ). (2016)
  • Author(s): Nakamura Y, Miyagawa F, Okazaki A, Okuno Y, Mori Y, Iso H, Yamanishi K, Asada H
  • Journal Title: J Am Acad Dermatol Volume: 75 Issue: 5 Pages: 950-956
  • DOI: 10.1016/j.jaad.2016.05.037
  • Peer Reviewed
• [Journal Article] Involvement of HHV-6 infection in renal dysfunction associated with DIHS/DRESS. (2016)
  • Author(s): Miyashita K, Shobatake C, Miyagawa F, Kobayashi N, Onmori R, Yonekawa S, Tanabe K, Kawate K, Morita K, Asada H
  • Journal Title: Acta Derm Venereol Volume: 96 Issue: 1 Pages: 114-5
  • DOI: 10.2340/00015555-2149
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Adult case of staphylococcal scalded skin syndrome differentiated from toxic epidermal necrolysis with the aid of dermoscopy. (2016)
  • Author(s): Miyashita K, Ogawa K, Iioka H, Miyagawa F, Okazaki A, Kobayashi N, Asada H
  • Journal Title: J Dermatol Volume: - Issue: 7 Pages: 842-843
  • DOI: 10.1111/1346-8138.13281
  • Peer Reviewed
• [Journal Article] A case of CD8+ primary cutaneous peripheral T-cell lymphoma arising from tissue-resident memory T (TRM) cells in the skin. (2015)
  • Author(s): Miyagawa F, Iioka H, Fukumoto T, Kobayashi N, Asada H
  • Journal Title: Br J Dermatol Volume: 173 Issue: 2 Pages: 612-614
  • DOI: 10.1111/bjd.13687
  • Peer Reviewed
• [Journal Article] Hypersensitivity to influenza vaccine in a case of Epstein-Barr virus-associated T lymphoproliferative disorder. (2015)
  • Author(s): Himuro Y, Miyagawa F, Fukumoto T, Hasegawa M, Kobayashi N, Asada H
  • Journal Title: Br J Dermatol Volume: - Issue: 6 Pages: 1686-1688
  • DOI: 10.1111/bjd.13713
  • Peer Reviewed
• [Journal Article] Efficacy of additional i.v. immunoglobulin to steroid therapy in Stevens-Johnson syndrome and toxic epidermal necrolysis. (2015)
  • Author(s): Aihara M, Kano Y, Fujita H, Kambara T, Matsukura S, Katayama I, Azukizawa H, Miyachi Y, Endo Y, Asada H, Miyagawa F, Morita E, Kaneko S, Abe R, Ochiai T, Sueki H, Watanabe H, Nagao K, Aoyama Y, Sayama K, Hashimoto K, Shiohara T
  • Journal Title: J Dermatol Volume: 42 Pages: 768-77
  • Peer Reviewed
• [Journal Article] VZV skin-test reaction, but not antibody, is an important predictive factor for postherpetic neuralgia. (2015)
  • Author(s): Imoto K, Okazaki A, Onishi F, Miyazaki Y, Okeda M, Yano S, Takao Y, Gomi Y, Ishikawa T, Okuno Y, Mori Y, Iso H, Yamanishi K, Asada H
  • Journal Title: J Dermatol Sci Volume: 79 Issue: 3 Pages: 235-40
  • DOI: 10.1016/j.jdermsci.2015.05.011
  • Peer Reviewed
• [Journal Article] Incidences of Herpes Zoster and Postherpetic Neuralgia in Japanese Adults Aged 50 Years and Older From a Community-based Prospective Cohort Study: The SHEZ Study (2015)
  • Author(s): Takao Y, Miyazaki Y, Okeda M, Onishi F, Yano S, Gomi Y, Ishikawa T, Okuno Y, Mori Y, Asada H, Yamanishi K, Iso H
  • Journal Title: Journal of Epidemiology Volume: 25 Issue: 10 Pages: 617-625
  • DOI: 10.2188/jea.JE20140210
  • NAID: 130005107958
  • ISSN: 0917-5040, 1349-9092
  • Peer Reviewed
• [Journal Article] Differential expression profile of Th1/Th2-associated chemokines characterizes Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug-induced hypersensitivity syndrome /drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) as distinct entities. (2015)
  • Author(s): Miyagawa F, Hasegawa A, Imoto K, Ogawa K, Kobayashi N, Ito K, Fujita H, Aihara M, Watanabe H, Sueki H, Tohyama M, Asada H
  • Journal Title: Eur J Dermatol Volume: 25 Issue: 1 Pages: 87-9
  • DOI: 10.1684/ejd.2014.2477
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Sequelae in 145 patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms: Survey conducted by the Asian Research Committee on Severe Cutaneous Adverse Reactions (ASCAR) (2015)
  • Author(s): Kano Y, Tohyama M, Aihara M, Matsukura S, Watanabe H, Sueki H, Iijima M, Morita E, Niihara H, Asada H, Kabashima K, Azukizawa H, Hashizume H, Nagao K, Takahashi H, Abe R, Sotozono C, Kurosawa M, Aoyama Y, Chu CY, Chung WH, Shiohara T
  • Journal Title: Journal of Dermatology Volume: 42 Issue: 3 Pages: 276-282
  • DOI: 10.1111/1346-8138.12770
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Involvement of HHV-6 infection in renal dysfunction associated with DIHS/DRESS. (2015)
  • Author(s): Miyashita K, Shobatake C, Miyagawa F, Kobayashi N, Onmori R, Yonekawa S, Tanabe K, Kawate K, Morita K, Asada H
  • Journal Title: Acta Derm Venereol Volume: -
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Increased ratio of FoxP3+ regulatory T cells/CD3+ T cells in skin lesions in drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms. (2014)
  • Author(s): Morito H, Ogawa K, Fukumoto T, Kobayashi N, Morii T, Kasai T, Nonomura A, Kishimoto T, Asada H
  • Journal Title: Clin Exp Dermatol Volume: 39 Issue: 3 Pages: 284-91
  • DOI: 10.1111/ced.12246
  • Peer Reviewed
• [Journal Article] Elevated serum thymus and activation-regulated chemokine (TARC/CCL17) relates to reactivation of human herpesvirus 6 in drug reactions with eosinophilia and systemic symptoms (DRESS)/ drug-induced hypersensitivity syndrome (DIHS). (2014)
  • Author(s): Ogawa K, Morito H, Hasegawa A, Miyagawa F, Kobayashi N, Watanabe H, Sueki H, Tohyama M, Hashimoto K, Kano Y, Shiohara T, Ito K, Fujita H, Aihara M, Asada H
  • Journal Title: Br J Dermatol Volume: - Issue: 2 Pages: 425-427
  • DOI: 10.1111/bjd.12948
  • Peer Reviewed / Open Access
• [Journal Article] Epidermal growth factor receptor inhibitors selectively inhibit the expression of human β-defensins induced by Staphylococcus epidermidis. (2014)
  • Author(s): Park K, Ommori R, Imoto K, Asada H
  • Journal Title: J Dermatol Sci Volume: 75 Issue: 2 Pages: 94-9
  • DOI: 10.1016/j.jdermsci.2014.04.011
  • Peer Reviewed
• [Journal Article] Usefulness of ultrasonography for rapidly diagnosing cutaneous sinus tracts of dental origin (2014)
  • Author(s): Shobatake C, Miyagawa F, Fukumoto T, Hirai T, Kobayashi N, Asada H
  • Journal Title: Eur J Dermatol Volume: 24 Issue: 6 Pages: 683-687
  • DOI: 10.1684/ejd.2014.2441
  • Peer Reviewed
• [Presentation] Up-regulation of HHV-6 microRNAs in the serum of DIHS/DRESS patients (2016)
  • Author(s): Miyashita K, Miyagawa F, Nakamura Y, Onmori R, Azukizawa H, Asada H
  • Organizer: 第41回日本研究皮膚科学会学術大会・総会
  • Place of Presentation: 仙台市
  • Year and Date: 2016-12-09
• [Presentation] The characteristics of patients with persistent HHV-6 infection after drug-induced hypersensitivity syndrome (DIHS) (2016)
  • Author(s): Nakamura Y, Miyashita K, Onmori R, Miyagawa F, Azukizawa H, Asada H
  • Organizer: 第41回日本研究皮膚科学会学術大会・総会
  • Place of Presentation: 仙台市
  • Year and Date: 2016-12-09
• [Presentation] DIHSについて最近わかってきたこと (2016)
  • Author(s): 浅田秀夫
  • Organizer: 80回日本皮膚科学会東部支部企画研修講習会
  • Place of Presentation: 浜松市
  • Year and Date: 2016-10-29
  • Invited
• [Presentation] DIHS の診断（ウイルス再活性化，TARC を含めて） (2016)
  • Author(s): 宮川史、浅田秀夫
  • Organizer: 第115回日本皮膚科学会総会
  • Place of Presentation: 京都市
  • Year and Date: 2016-06-03
  • Invited
• [Presentation] Preferential expression of CD134, HHV-6 cellular receptor, on CD4 T cells in drug-induced hypersensitivity syndrome (2015)
  • Author(s): Miyagawa F, Nakamura Y, Asada H
  • Organizer: The 40th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: Okayama
  • Year and Date: 2015-12-11
• [Presentation] 薬疹のバイオマーカー (2015)
  • Author(s): 浅田秀夫
  • Organizer: 第45回日本皮膚アレルギー・接触皮膚炎学会
  • Place of Presentation: 松江市
  • Year and Date: 2015-11-20
  • Invited
• [Presentation] 薬剤性過敏症症候群患者の末梢血単核球におけるHHV-6受容体の解析 (2015)
  • Author(s): 宮川 史、中村友紀、浅田秀夫
  • Organizer: 第45回日本皮膚アレルギー・接触皮膚炎学会
  • Place of Presentation: 松江市
  • Year and Date: 2015-11-20
• [Presentation] 皮膚科領域のヘルペスウイルス感染症－最近の話題を中心に (2015)
  • Author(s): 浅田秀夫
  • Organizer: 第80回 日本皮膚科学会山梨地方会
  • Place of Presentation: 甲府市
  • Year and Date: 2015-04-04
  • Invited
• [Presentation] ウイルスと薬疹の接点 (2014)
  • Author(s): 浅田秀夫
  • Organizer: 総合アレルギー講習会
  • Place of Presentation: 横浜
  • Year and Date: 2014-12-20 – 2014-12-21
  • Invited
• [Presentation] Involvement of HHV-6 infection in renal dysfunction associated with DIHS. (2014)
  • Author(s): Miyashita K, Shoubatake C, Miyagawa F, Kobayashi N, Onmori R, Asada H
  • Organizer: The 39th Annual Meeting of the Japanease Society for Investigative Dermatology
  • Place of Presentation: 大阪
  • Year and Date: 2014-12-12 – 2014-12-14
• [Presentation] HHV-6の持続感染の関与が疑われた紅皮症の1例 (2014)
  • Author(s): 光井康博、大黒奈津子、御守里絵、小川浩平、小林信彦、浅田秀夫
  • Organizer: 第44回日本皮膚アレルギー・接触皮膚炎学会総会学術大会
  • Place of Presentation: 仙台
  • Year and Date: 2014-11-21 – 2014-11-23
• [Presentation] A case of acute renal failure related to DIHS due to TMP/SMX (2014)
  • Author(s): Miyashita K, Shoubatake C, Miyagawa F, Kobayashi N, Onmori R, Yonekawa S, Tanabe K, Kawate K, Morita K, Asada H
  • Organizer: 39th Annual International Herpesvirus Workshop
  • Place of Presentation: 神戸
  • Year and Date: 2014-07-19 – 2014-07-23
• [Presentation] 重症薬疹診断のバイオマーカー (2014)
  • Author(s): 小川浩平、浅田秀夫
  • Organizer: 第113回 日本皮膚科学会総会
  • Place of Presentation: 京都
  • Year and Date: 2014-05-30 – 2014-06-01
  • Invited
• [Presentation] 急性腎障害を伴い透析導入を要した薬剤性過敏症症候群(DIHS)の1例 (2014)
  • Author(s): 宮下和也、正畠千夏、小川浩平、飯岡弘至、米川真輔、田邊香、川手健次、岡崎愛子、小林信彦、浅田秀夫
  • Organizer: 第113回 日本皮膚科学会総会
  • Place of Presentation: 京都
  • Year and Date: 2014-05-30 – 2014-06-01
• [Book] 薬疹の診断と治療アップデート～重症薬疹を中心に～ 薬疹とウイルス (2015)
  • Author(s): 浅田秀夫
  • Publisher: 医薬ジャーナル社