Comprehensive analysis of pathogenesis of cutaneous lymphoma

2017 Fiscal Year Annual Research Report

• Project/Area Number: 16K19709
• Research Institution: The University of Tokyo
• Principal Investigator: 宮垣 朝光 東京大学, 医学部附属病院, 助教 (50582003)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Keywords: 皮膚T細胞リンパ腫 / 菌状息肉症 / セザリー症候群 / cyclophilin A / CD147 / ERK / IL-10産生制御性B細胞 / CD137-CD137L

Outline of Annual Research Achievements

昨年度、我々は、cutaneous T-cell lymphoma (CTCL)の腫瘍細胞がcyclophilin Aを分泌し、自身が発現しているCD147に結合し、腫瘍細胞の増殖を促していることを報告した。本年度、我々はその増殖にERK経路が重要であることを見出した。さらに、cyclophilin Aの阻害剤やCD147の中和抗体はin vivoにおける腫瘍細胞の増殖を抑制することができた。以上より、cyclophilin A-CD147の相互関係の阻害はCTCLの新たな治療戦略になると考えた。
続いて、CTCL患者の末梢血中におけるIL-10産生制御性B細胞について、解析を行った。CTCL患者の末梢血中ではIL-10産生制御性B細胞の数、割合が減少しており、病勢マーカーと逆相関を認めた。IL-10はCTCLの腫瘍細胞の増殖を抑える可能性が報告されており、IL-10産生制御性B細胞の減少がCTCLの病態に関わっている可能性が示唆された。
また、我々は免疫チェックポイント分子であるCD137、CD137Lに注目した。通常、CD137はT細胞やNK細胞に発現し、CD137Lは樹状細胞などの抗原提示細胞に発現している。CD137-CD137Lの相互関係はT細胞の活性化を誘導し、抗腫瘍免疫を増強することが知られている。今回、我々は、CTCLの腫瘍細胞がCD137に加えて、異所性にCD137Lを発現していることを見出した。さらに、中和抗体を用いて、その相互関係を阻害したところ、腫瘍細胞の増殖、生存、CXCR4を介した遊走能の低下がみられた。また、中和抗体はCTCLの細胞株をマウスに接種するtumor inoculation modelにおいて、in vivoにおける腫瘍の成育も阻害することができた。以上の結果から、CD137-CD137Lの相互関係を阻害することはCTCLの新たな治療につながると考えられた。

Research Products

• [Journal Article] Serum vascular endothelial growth factor A levels reflect itch severity in mycosis fungoides and Sezary 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: Journal of Dermatology Volume: 45 Pages: 95-99
  • DOI: 10.1111/1346-8138.14033.
  • Peer Reviewed
• [Journal Article] Interleukin-25 is involved in cutaneous T-cell lymphoma progression by establishing a T helper 2-dominant microenvironment. (2018)
  • Author(s): Nakajima R, Miyagaki T, Hirakawa M, Oka T, Takahashi N, Suga H, Yoshizaki A, Fujita H, Asano Y, Sugaya M, Sato S
  • Journal Title: British Journal of Dermatology Volume: 未収載 Pages: 未収載
  • DOI: 10.1111/bjd.16237.
  • 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 Pages: 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 Pages: 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 Pages: 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 Pages: 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 Pages: 未収載
  • Peer Reviewed
• [Journal Article] Serum soluble CD48 levels as a prognostic marker in mycosis fungoides and Sezary syndrome. (2018)
  • Author(s): Oka T, Miyagaki T, Takahashi N, Nakajima R, Kamijo H, Suga H, Asano Y, Sugaya M, Sato S
  • Journal Title: Journal of Investigative Dermatology Volume: 未収載 Pages: 未収載
  • 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 Pages: 未収載
  • DOI: 10.1016/j.jid.2018.03.1520.
  • Peer Reviewed
• [Journal Article] Increased 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: Journal of Dermatology Volume: 44 Pages: 1392-1395
  • DOI: 10.1111/1346-8138.13974.
  • 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