Elucidation of immunostimulatory mechanism of IMiDs and antibody-drugs for optimized myeloma treatment

• Project/Area Number: 17K09963
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kansai Medical University
• Principal Investigator: ITO Tomoki 関西医科大学, 医学部, 准教授 (70434826)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: IMiDs / type I IFNs / Th2 immune response / allergy / multiple myeloma / antibody drugs / dendritic cells / CCL17 / 樹状細胞 / エロツズマブ / カルフィルゾミブ / イキサゾミブ / 多発性骨髄腫 / IFN-alpha / IFN-a / Th2 / 内科 / 免疫学

Outline of Final Research Achievements

We demonstrated that lenalidomide could sustain and potentially enhance IFN-alpha production from plasmacytoid dendritic cells (DCs). In addition, IMiDs suppressed the Th1-inducing capacity of myeloid DCs, instead promoting a Th2 response. The lenalidomide-associated rashes might be a result of an allergic response driven by Th2-axis activation. Our findings suggest clinical efficacy and rashes as a side effect of IMiDs are inextricably linked through immunostimulation. Thus, IMiDs enhances the DC-mediated IFN-alpha response and Th2 immune response, contributing to immune activation. As multiple myeloma is characterized by immune dysfunction involved in prognosis, our findings unveiled a novel target of IMiDs. IMiDs have the DC-mediated immunostimulatory activities, leading to amplification of a positive immune axis able to eliminate MM cells.

Academic Significance and Societal Importance of the Research Achievements

免疫調節薬IMiDsという薬剤が、なぜ多発性骨髄腫に対し効くのか？その免疫学的解析を樹状細胞という免疫システムの司令官をターゲットとして解明し得たことが学術的意義と言える。また、この薬剤を使用した場合、有害事象の皮疹が出ると、実は潜在的に治療効果が高い可能性があることが示された。この結果は、実臨床で非常に有益な情報と考えられ社会的意義があると考える。

Research Products

• [Journal Article] Immunomodulatory Drugs and Plasmacytoid Dendritic Cells: Cooperation in Multiple Myeloma Treatment (2020)
  • Author(s): ③Ito T.
  • Journal Title: Journal of Blood Transfusions and Diseases Volume: 3 Pages: 136-143
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Immunomodulatory drugs suppress Th1-inducing ability of dendritic cells but enhance Th2-mediated allergic responses. (2020)
  • Author(s): ②Vien P, Ito T et al.
  • Journal Title: Blood ADV. Volume: In press
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The immunomodulatory-drug, lenalidomide, sustains and enhances interferon-α production by human plasmacytoid dendritic cells (2019)
  • Author(s): Kibata Kayo, Ito Tomoki, Inaba Muneo, Tanaka Akihiro, Iwata Ryoichi, Inagaki-Katashiba Noriko, Phan Vien, Satake Atsushi, Nomura Shosaku
  • Journal Title: Jounal of Blood Medicine Volume: 10 Pages: 217-226
  • DOI: 10.2147/jbm.s206459
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Elotuzumab enhances the Th2-mediated immune response of dendritic cell induced by Immunomodulatory Drugs (IMiDs). (2019)
  • Author(s): Azuma Y
  • Organizer: 61th American Society of Hematology Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] Elotuzumab has the ability to enhance dendritic cell-mediated Th2 cell response (2019)
  • Author(s): Azuma Y
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] Myeloma cells have the ability to suppress Th1-inducing capacity but enhance Th2-mediated response of dendritic cells by producing factors other than soluble SLAMF7 (2019)
  • Author(s): Azuma Y
  • Organizer: 第44回日本骨髄腫学術集会
• [Presentation] e: Myeloma cells have the ability to suppress Th1-inducing capacity but enhance Th2-mediated response of dendritic cells by producing factors other than soluble SLAMF7 (2018)
  • Author(s): Yoshiko Azuma
  • Organizer: The 61th American Society of Hematology (ASH) Annual Meeting(国際学会)
  • Int'l Joint Research
• [Presentation] Short-term exposure to a high concentration of carfilzomib stimulates plasmacytoid dendritic cells (2018)
  • Author(s): Yuta Yamanaka
  • Organizer: 日本血液学会
• [Presentation] Clinical troughconcentration of ixazomibdoes not suppressfunction of human dendritic cell subsets (2018)
  • Author(s): Yusuke Sawai
  • Organizer: 日本血液学会
• [Presentation] Lenalidomide Acts As a Positive Immunomodulator through Modulating the Functions of Human Plasmacytoid Dendritic Cells (2017)
  • Author(s): Tomoki Ito
  • Organizer: The 60th American Society of Hematology (ASH) Annual Meeting
  • Int'l Joint Research
• [Remarks] 関西医科大学内科学第一講座
  • URL: http://imed1.kmu-ac.jp/index.html