Comprehensive analysis of pathogenesis of cutaneous lymphoma

• Project/Area Number: 16K19709
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Dermatology
• Research Institution: The University of Tokyo
• Principal Investigator: Miyagaki Tomomitsu 東京大学, 医学部附属病院, 講師 (50582003)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 皮膚悪性リンパ腫 / 菌状息肉症 / セザリー症候群 / IL-25 / cyclophilin A / CD147 / IL-10産生制御性B細胞 / CD137-CD137L / 皮膚T細胞リンパ腫 / ERK / Th2優位の微小環境 / オートクリン / 腫瘍微小環境 / B細胞 / 自己分泌因子

Outline of Final Research Achievements

We examined the expression and involvement of IL-25, cyclophilin A, CD147, CD137, CD137L, and IL-10-producing regulatory B cells (Bregs) in cutaneous T-cell lymphoma (CTCL).
We found that Th2 cytokines highly expressed in CTCL lesional skin induced IL-25 production by epidermal keratinocytes, which may in turn lead to formation of Th2-dominant microenvironment through the direct induction of IL-13 by tumor cells. We also found that interactions between CD147 expressed on the cell surface of CTCL tumor cells and CypA secreted by those cells promote CTCL development through promoting proliferation and survival of tumor cells. Moreover, in addition to CD137, aberrant CD137L expression was found on tumor cells of CTCL, and CD137-CD137L interactions promote cell proliferation and migration in CTCL cells. Furthermore, the development of IL-10-producing Bregs is impaired in patients with advanced mycosis fungoides and the number of Bregs was inversely correlated with disease severity markers.

Research Products

• [Journal Article] Serum vascular endothelial growth factor A levels reflect itch severity in mycosis fungoides and Sézary syndrome. (2018)
  • Author(s): Sakamoto M, Miyagaki T, Kamijo H, Oka T, Takahashi N, Suga H, Yoshizaki A, Asano Y, Sugaya M, Sato S.
  • Journal Title: J Dermatol Volume: 45 Issue: 1 Pages: 95-99
  • DOI: 10.1111/1346-8138.14033
  • Peer Reviewed
• [Journal Article] Decreased IL-10-producing regulatory B cells in patients with advanced mycosis fungoides. (2018)
  • Author(s): Akatsuka T, Miyagaki T, Nakajima R, Kamijo H, Oka T, Takahashi N, Suga H, Yoshizaki A, Asano Y, Sugaya M, Sato S
  • Journal Title: European Journal of Dermatology Volume: 未収載
  • Peer Reviewed
• [Journal Article] Methotrexate-associated lymphoproliferative disorder presenting as giant ulcers on the leg. (2018)
  • Author(s): Oka T, Miyagaki T, Nakamura R, Funamizu K, Sugaya M, Ebisawa K, Koya J, Kurokawa M, Sato S
  • Journal Title: Clinical and Experimental Dermatology Volume: 未収載
  • Peer Reviewed
• [Journal Article] HMGB1 levels are increased in lesional skin and sera in patients with cutaneous T-cell lymphoma. (2018)
  • Author(s): Senda N, Miyagaki T, Kamijo H, Nakajima R, Oka T, Takahashi N, Suga H, Yoshizaki A, Asano Y, Sugaya M, Sato S
  • Journal Title: European Journal of Dermatology Volume: 未収載
  • Peer Reviewed
• [Journal Article] A case of folliculotropic mycosis fungoides successfully treated with topical steroid treatment. (2018)
  • Author(s): Numajiri H, Miyagaki T, Sugaya M, Sato S
  • Journal Title: Journal of Cancer Research and Therapeutics Volume: 未収載
  • Peer Reviewed
• [Journal Article] Linear IgA bullous dermatosis limited to oral mucosa associated with ulcerative colitis. (2018)
  • Author(s): Oka T, Miyagaki T, Isomura S, Ichimura Y, Kamata M, Mitsui H, Ishii N, Hashimoto T, Sato S
  • Journal Title: Journal of Dermatology Volume: 未収載
  • Peer Reviewed
• [Journal Article] Serum soluble CD48 levels as a prognostic marker in mycosis fungoides and Sézary syndrome. (2018)
  • Author(s): Oka T, Miyagaki T, Takahashi N, Nakajima R, Kamijo H, Suga H, Asano Y, Sugaya M, Sato S.
  • Journal Title: J Invest Dermatol Volume: Epub ahead of print Issue: 10 Pages: 2286-2288
  • DOI: 10.1016/j.jid.2018.03.1519
  • Peer Reviewed
• [Journal Article] Exacerbated immune complex-mediated vascular injury in mice with heterozygous deficiency of Aryl hydrocarbon receptor through upregulation of Fcγ receptor III expression on macrophages. (2018)
  • Author(s): Nakajima R, Miyagaki T, Morimura S, Fukasawa T, Oka T, Yoshizaki A, Sugaya M, Sato S
  • Journal Title: Journal of Investigative Dermatology Volume: 未収載 Issue: 10 Pages: 2195-2204
  • DOI: 10.1016/j.jid.2018.03.1520
  • Peer Reviewed
• [Journal Article] ncreased endocan expression in lesional skin and decreased endocan expression in sera in atopic dermatitis. (2017)
  • Author(s): Ｓuzuki H, Miyagaki T, Otobe S, Nakajima R, Oka T, Takahashi N, Kabasawa M, Suga H, Yoshizaki A, Asano Y, Sato S, Sugaya M.
  • Journal Title: J Dermatol Volume: 44 Issue: 12 Pages: 1392-1395
  • DOI: 10.1111/1346-8138.13974
  • Peer Reviewed
• [Journal Article] IL-25 is involved in CTCL progression by establishing Th2-dominant microenvironment (2017)
  • Author(s): Nakajima R.、Miyagaki T.、Oka T.、Takahashi N.、Hirakawa M.、Suga H.、Yoshizaki A.、Fujita H.、Asano Y.、Sugaya M.、Sato S.
  • Journal Title: Br J Dermatol Volume: ｉｎ ｐｒｅｓｓ Issue: 6 Pages: 1373-1382
  • DOI: 10.1111/bjd.16237
  • Peer Reviewed
• [Journal Article] Placental growth factor and vascular endothelial growth factor together regulate tumor progression via increased vasculature in cutaneous T-cell lymphoma. (2017)
  • Author(s): Miyagaki T, Sugaya M, Oka T, Takahashi N, Kawaguchi M, Suga H, Fujita H, Yoshizaki A, Asano Y, Sato S.
  • Journal Title: Acta Derm Venereol Volume: 未定 Issue: 5 Pages: 586-592
  • DOI: 10.2340/00015555-2623
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A Case of Mycosis Fungoides with Gastric and Central Nervous System Involvement. (2017)
  • Author(s): Senda N, Miyagaki T, Oka T, Ito Y, Katayama K, Kamiyama T, Sugaya M, Sato S
  • Journal Title: J Dermatol Volume: 未定 Issue: 7
  • DOI: 10.1111/1346-8138.13820
  • Peer Reviewed
• [Presentation] Th2-dominant microenvironment by IL-25 in cutaneous T-cell lymphoma. (2017)
  • Author(s): Miyagaki T, Nakajima R, Oka T, Takahashi N, Hirakawa M, Suga H, Fujita H, Sugaya M, Sato S
  • Organizer: The 76th Annual Meeting of the SID
  • Int'l Joint Research
• [Presentation] 進行期菌状息肉症患者における末梢血中制御性B細胞の解析 (2017)
  • Author(s): 宮垣 朝光，岡 知徳，高橋 菜穂美，管 析，菅谷 誠，佐藤 伸一
  • Organizer: 第45回日本臨床免疫学会
• [Presentation] CD147-cyclophilin A interactions promote proliferation of cutaneous T-cell lymphoma (2017)
  • Author(s): Sakamoto M, Miyagaki T, Kamijo H, Oka T, Takahashi N, Suga H, Suagya M, Sato S
  • Organizer: The 47th Annual ESDR Meeting
  • Int'l Joint Research
• [Presentation] Blocking CD137-CD137L interactions inhibits proliferation and survival of cutaneous T-cell lymphoma cells via hampering several signaling pathways (2017)
  • Author(s): Kamijo H, Miyagaki T, Oka T, Takahashi N, Suga H, Sugaya M, Sato S
  • Organizer: The 47th Annual ESDR Meeting
  • Int'l Joint Research
• [Presentation] Galectin-9 induces apoptosis of tumor cells through caspase pathways in cutaneous T-cell lymphoma (2017)
  • Author(s): Nakajima R, Miyagaki T, Kamijo H, Oka T, Takahashi N, Suga H, Suagya M, Sato S
  • Organizer: The 47th Annual ESDR Meeting
  • Int'l Joint Research
• [Presentation] HMGB1 levels are increased in lesional skin and sera in patients with erythrodermic cutaneous T-cell lymphoma (2017)
  • Author(s): Senda N, Miyagaki T, Kamijo H, Oka T, Takahashi N, Suga H, Suagya M, Sato S
  • Organizer: The 47th Annual ESDR Meeting
  • Int'l Joint Research
• [Presentation] Decreased IL-10-producing regulatory B cells in advanced mycosis fungoides (2017)
  • Author(s): Miyagaki T, Akatsuka T, Nakajima R, Kamijo H, Oka T, Takahashi N, Suga H, Suagya M, Sato S
  • Organizer: The 42nd Annual Meeting of the JSID
• [Presentation] Decreased GPNMB expression is involved in the development of psoriasis (2017)
  • Author(s): Akatsuka T, Miyagaki T, Oka T, Suga H, Yoshizaki A, Asano Y, Sugaya M, Sato S
  • Organizer: The 42nd Annual Meeting of the JSID
• [Presentation] Increased CD244 and CD48 expression in cutaneous T-cell lymphoma (2017)
  • Author(s): Oka T, Miyagaki T, Takahashi N, Kamijo H, Nakajima R, Suga H, Sugaya M, Sato S
  • Organizer: The 42nd Annual Meeting of the JSID
• [Presentation] CX3CR1 Deficiency Attenuates DNFB-induced Contact Hypersensitivity (2017)
  • Author(s): Otobe S, Miyagaki T, Sugaya M, Sato S
  • Organizer: The 42nd Annual Meeting of the JSID
• [Presentation] CD147-cyclophilin A interactions promote proliferation and survival of cutaneous T-cell lymphoma (2017)
  • Author(s): Sakamoto M, Miyagaki T, Kamijo H, Oka T, Takahashi N, Suga H, Suagya M, Sato S
  • Organizer: The 42nd Annual Meeting of the JSID
• [Presentation] Blocking CD137-CD137L interactions inhibits proliferation and survival of cutaneous T-cell lymphoma cell lines and tumor cells via hampering several signaling pathways (2017)
  • Author(s): Kamijo H, Miyagaki T, Oka T, Takahashi N, Suga H, Sugaya M, Sato S
  • Organizer: The 42nd Annual Meeting of the JSID
• [Presentation] Decreased progranulin expression in cutaneous T-cell lymphoma and atopic dermatitis (2017)
  • Author(s): Nakajima R, Miyagaki T, Kamijo H, Otobe S, Akatsuka T, Oka T, Takahashi N, Suga H, Sugaya M, Sato S
  • Organizer: The 42nd Annual Meeting of the JSID
• [Presentation] Increased YKL-40 expression in cutaneous T-cell lymphoma (2017)
  • Author(s): Suzuki H, Miyagaki T, Oka T, Akastuka T, Kamijo H, Nakajima R, Takahashi N, Suga H, Sugaya M, Sato S
  • Organizer: The 42nd Annual Meeting of the JSID
• [Presentation] Anaplastic large cell lymphoma involving skin and muscle associated with polymyositis. (2016)
  • Author(s): Miyagaki T, Sugaya M, Hayashi Y, Nakamura K, Takahashi N, Asano Y, Sato S, Koguchi A, Yamaguchi N, Ueda J, Shimizu J, Taoka K, Kurokawa M
  • Organizer: Third World Congress of Cutaneous Lymphomas
  • Place of Presentation: New York, USA
  • Year and Date: 2016-10-27
  • Int'l Joint Research
• [Presentation] Aryl Hydrocarbon Receptor Deficiency Exacerbates Immune Complex-Mediated Vascular Injury Through Up-regulation of CD16 Expression on Macrophages (2016)
  • Author(s): Nakajima R, Miyagaki T, Kabasawa M, Morimura S, Sugaya M, Sato S
  • Organizer: The 46th Annual Meeting of the European Society for Dermatological Research
  • Place of Presentation: Munich, Germany
  • Year and Date: 2016-09-07
  • Int'l Joint Research
• [Presentation] Vascular endothelial growth factor (VEGF)-A and placental growth factor (PlGF) regulate tumor progression via increased vasculature in cutaneous T cell lymphoma (CTCL). (2016)
  • Author(s): Miyagaki T, Sugaya M, Oka T, Takahashi N, Kawaguchi M, Suga H, Fujita H, Yoshizaki A, Asano Y, Sato S
  • Organizer: International Congress of Immunology 2016
  • Place of Presentation: Melbourne, Australia
  • Year and Date: 2016-08-21
  • Int'l Joint Research