Study of skin innate immune response in cutaneous adverse effects caused by molecular targeted agents

• Project/Area Number: 18K16037
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53050:Dermatology-related
• Research Institution: Nara Medical University
• Principal Investigator: OMMORI RIE 奈良県立医科大学, 医学部, 特任助教 (20533722)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: EGFR阻害薬 / 分子標的治療薬 / 薬疹 / ざ瘡様皮疹 / 自然免疫応答 / 抗菌ペプチド / human β-defensin

Outline of Final Research Achievements

Epidermal growth factor receptor inhibitors (EGFRIs) are a well-established targeted therapy for several cancers, and these drugs frequently cause cutaneous adverse effects such as papulo-pustular eruptions. However, the mechanism of the reactions remains unclear. In the present study, we investigated whether EGFRIs have an influence on innate immune response in patients’ skin to reveal the pathological mechanism of cutaneous adverse reactions caused by EGFRIs. We found that human β-defensin(hBD)1 and hBD3 were significantly decreased in patients with papulo-pustular eruptions. Our results may suggest that a reduction in hBD contributes to the increased incidence of papulo-pustular eruptions.

Academic Significance and Societal Importance of the Research Achievements

本研究の結果、EGFR阻害薬によるざ瘡様皮疹発症にはβ-defensinが非常に強く関与し、β-defensin産生抑制効果が、EGFR阻害薬による皮膚症状の病態形成にかかわっている可能性が示唆された。このことから、将来的にはβ-defensin含有外用薬などにより患者皮膚局所のβ-defensinを補充することで、ざ瘡様皮疹の発症を予防できる可能性が示された。

Research Products

• [Journal Article] Reduced induction of human β-defensins is involved in the pathological mechanism of cutaneous adverse effects caused by epidermal growth factor receptor monoclonal antibodies. (2020)
  • Author(s): Ommori R, Nakamura Y, Miyagawa F, Shobatake C, Ogawa K, Koyama F, Sho M, Ota I, Kitahara T, Hontsu S, Muro S, Asada H
  • Journal Title: Clin Exp Dermatol Volume: 45 Issue: 8 Pages: 1055-1058
  • DOI: 10.1111/ced.14311
  • Peer Reviewed
• [Journal Article] Predominant contribution of CD4 T cells to human herpesvirus 6 (HHV-6) load in the peripheral blood of patients with drug-induced hypersensitivity syndrome and persistent HHV-6 Infection. (2018)
  • Author(s): Miyagawa F, Nakamura Y, Ommori R, Miyashita K, Iioka H, Miyashita N, Nishikawa M, Himuro Y, Ogawa K, Asada H
  • Journal Title: Acta Derm Venereol Volume: 98 Issue: 1 Pages: 146-148
  • DOI: 10.2340/00015555-2791
  • Peer Reviewed / Open Access
• [Journal Article] Serum thymus and activation-regulated chemokine is associated with the severity of drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome. (2018)
  • Author(s): Nakamura-Nishimura Y, Miyagawa F, Miyashita K, Ommori R, Azukizawa H, Asada H
  • Journal Title: Br J Dermatol Volume: 178 Issue: 6 Pages: 1430-1432
  • DOI: 10.1111/bjd.16132
  • Peer Reviewed / Open Access
• [Journal Article] Up-regulation of human herpesvirus 6B-derived microRNAs in the serum of patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms. (2018)
  • Author(s): 3.Miyashita K, Miyagawa F, Nakamura Y, Onmori R, Azukizawa H, Asada H
  • Journal Title: Acta Derm Venereol Volume: 98 Issue: 6 Pages: 612-613
  • DOI: 10.2340/00015555-2925
  • 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
• [Presentation] Reduced induction of human β-defensins is involved in the pathological mechanism of cutaneous adverse effects caused by EGFR monoclonal antibodies (2020)
  • Author(s): Rie Ommori, Yuki Nakamura, Fumi Miyagawa, Chinatsu Shobatake, Kohei Ogawa, Fumikazu Koyama, Masayuki Sho, Ichiro Ota, Tadashi Kitahara, Shigeto Hontsu, Sigeo Muro, Hideo Asada.
  • Organizer: 45th Annual Meeting of JSID（国際学会）
  • Int'l Joint Research
• [Presentation] 表皮自然免疫応答に着目したEGFR阻害薬による薬疹の病態解明 (2020)
  • Author(s): 御守里絵、西村友紀、正畠千夏、小川浩平、宮川史、浅田秀夫
  • Organizer: 第50回日本皮膚免疫アレルギー学会総会学術大会
• [Presentation] Human β-defensins are involved with pathological mechanism of cutaneous adverse effects caused by EGFR inhibitors. (2019)
  • Author(s): Rie Ommori, Fumi Miyagawa, Hiroaki Azukizawa, Hideo Asada
  • Organizer: 49th ESDR Annual Meeting
  • Int'l Joint Research
• [Presentation] Human β-defensins are involved with pathological mechanism of cutaneous adverse effects caused by EGFR inhibitors. (2019)
  • Author(s): Rie Ommori, Fumi Miyagawa, Hiroaki Azukizawa, Hideo Asada
  • Organizer: 44th Annual Meeting of the JSID
  • Int'l Joint Research
• [Presentation] EGFR阻害薬による皮膚障害の発症機序 (2018)
  • Author(s): 御守里絵
  • Organizer: 第48回日本皮膚免疫アレルギー学会総会学術大会
  • Invited