Elucidation of the pathogenic mechanism of acneiform skin eruptions caused by molecular targeted drugs
| Project/Area Number |
20K17357
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 53050:Dermatology-related
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| Research Institution | Nara Medical University |
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Principal Investigator |
Ommori Rie 奈良県立医科大学, 医学部, 特任助教 (20533722)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | human β-defensin / 抗菌ペプチド / 自然免疫応答 / 分子標的治療薬 / EGFR阻害薬 / ざ瘡様皮疹 / 薬疹 |
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| Outline of Research at the Start |
分子標的治療薬は種々の悪性腫瘍の治療に頻用されているが、その一方で、特徴的な薬疹が増加してきている。しかしその発症機序については未だ不明な点が多い。これまでにわれわれは、上皮成長因子受容体(EGFR)阻害薬が、培養ケラチノサイトの抗菌ペプチド産生を抑制することを明らかにした。本研究では、このEGFR阻害薬の皮膚自然免疫応答への影響に着目し、EGFR阻害薬投与患者皮膚における免疫関連分子、皮膚細菌叢と皮膚症状との相関を検討し、さらに培養細胞および動物モデルを用いて、EGFR阻害薬の自然免疫応答へ及ぼす影響のメカニズムを詳細に調べ、薬疹発症機序の一端を明らかし、その治療法、予防法の開発を目指す。
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| Outline of Final Research Achievements |
EGFR inhibitors (EGFRIs) are a well-established targeted therapy for several cancers, and these drugs frequently cause cutaneous adverse effects such as acneiform 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. In this study, we found that human β-defensin (hBD) was significantly decreased in patients with acneiform eruptions. S. epidermidis induced the expression of TGF-α in a TLR2-dependent manner, and subsequently produced hBD3 through EGFR signaling. EGFR signaling is necessary for hBD3 production induced by S. epidermidis. Our results suggest that S. epidermidis induce the expression of hBD3 via EGFR by inducing TGF-α under normal condition, but in patients treated with EGFRIs, hBD3 expression is significantly decreased, resulting in acneiform eruptions.
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| 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の発症にはβ-defensinの低下が密接に関与いる可能性が示唆された。平時ではブドウ球菌の感染はTGF-αとの相乗効果によりβ-defensinの発現を誘導することで、自然免疫応答を維持しているが、EGFR阻害剤を投与された患者においてはβ-defensin発現が著明に低下し、ざ瘡様皮疹が生じるのではないかと考えられた。
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Report
(4 results)
Research Products
(9 results)
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[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
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Journal Title
Clin Exp Dermatol
Volume: 45
Issue: 8
Pages: 1055-1058
DOI
Related Report
Peer Reviewed
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[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
Related Report
Int'l Joint Research
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