Importance of IL-23 to the Development of Elastase-Induced Pulmonary Inflammation and Emphysema

• Project/Area Number: 15K09221
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Okayama University
• Principal Investigator: Nobuaki Miyahara 岡山大学, 保健学研究科, 教授 (70335610)
• Co-Investigator(Kenkyū-buntansha): 金廣 有彦 岡山大学, 医学部, 客員研究員 (20243503)
• Research Collaborator: YOSHIMURA AKIHIKO 慶應義塾大学, 医学部微生物学免疫学
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: IL-23 / IL-17A / COPD / 肺気腫 / IL-17 / Th17 / エラスターゼ / p40

Outline of Final Research Achievements

The proliferation of T helper 17 (Th17) cells was induced by IL-23. To determine the contribution of IL-23 to the development of pulmonary emphysema a mouse model of PPE-induced emphysema was used in which responses of IL-23p19-deficient (IL-23-/-) and wild type (WT) mice were compared. Compared to WT mice, IL-23-/- mice developed markedly reduced emphysematous changes on histological analyses following PPE-instillation. These changes were associated with lower levels of IL-17A and fewer Th17 cells in the lung. The neutrophilia seen in bronchoalveolar lavage (BAL) fluid of WT mice was attenuated in IL-23-/- mice. Treatment with anti-IL-23p40 monoclonal antibody significantly attenuated PPE-induced emphysematous changes in the lungs of WT mice.
These data identify the important contributions of IL-23 to the development of elastase-induced pulmonary inflammation and emphysema. Targeting IL-23 in emphysema is a potential therapeutic strategy for delaying disease progression.

Academic Significance and Societal Importance of the Research Achievements

COPDにおいて、IL-17Aが肺気腫の進展に重要な役割を担っており、IL-23がIL-17Aを介して肺気腫の進展に関与していることが明らかとなった。抗IL-23抗体はヒトでは乾癬の治療薬としてすでに使用されており、また自己免疫性脳脊髄炎など様々な炎症性疾患マウスモデルにおける有用性が報告されている。これまで肺気腫への効果は全く不明であったが、本研究により抗IL-23抗体療法がCOPDの新規治療薬として、COPD患者の症状改善と年々増加している死亡者数の減少に極めて有用な治療となる可能性が考えられる。

Research Products

• [Int'l Joint Research] National Jewish Health(米国)
• [Journal Article] IL-23 is essential for the development of elastase-induced pulmonary inflammation and emphysema. (2016)
  • Author(s): Fujii U, Miyahara N,Taniguchi A, Waseda K, Morichika D, Kurimoto E, Koga H, Kataoka M, Gelfand EW, Cua DJ, Yoshimura A, Tanimoto M, Kanehiro A
  • Journal Title: Am J Respir Cell Mol Biol Volume: 55 Issue: 5 Pages: 697-707
  • DOI: 10.1165/rcmb.2016-0015oc
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] IL-23 is Essential to the Development of Elastase-induced Pulmonary Inflammation and Emphysema (2016)
  • Author(s): Utako Fujii, Nobuaki Miyahara, Akihiko Taniguchi, Koichi Waseda, Daisuke Morichika, Etsuko Kurimoto, Naohiro Oda, Hikari Koga, Mikio Kataoka, Akihiko Yoshimura, Mitsune Tanimoto, Arihiko Kanehiro
  • Organizer: The 56th Annual Meeting of Japanese Respiratory Society
  • Place of Presentation: 京都
  • Year and Date: 2016-04-09