Mechanism and therapy for immune suppression caused by severe infection and / or surgery.

• Project/Area Number: 18H02896
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 55050:Anesthesiology-related
• Research Institution: The University of Tokyo
• Principal Investigator: UCHIDA KANJI 東京大学, 医学部附属病院, 教授 (60302709)
• Co-Investigator(Kenkyū-buntansha): 山田 芳嗣 国際医療福祉大学, 国際医療福祉大学三田病院, 教授 (30166748) ; 比留間 孝広 東京大学, 医学部附属病院, 助教 (40572277)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2021: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2020: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
• Keywords: 敗血症 / 重症感染症 / 手術侵襲 / 免疫抑制 / 免疫賦活 / 重症感染 / 貪食能 / Innate immunity / GM-CSF / IFN-beta

Outline of Final Research Achievements

A mouse model of human septic peritonitis was created and the function of innate immune cells in the lungs and abdominal cavity was observed. In the model of moderate severity (about 10% mortality), the function of alveolar macrophages in the lungs was found to be suppressed, with reduced maturation marker expression, even on day 4, where mice were in the recovery period. Impaired function and maturity were restored by systemic IFNβ administration or transtracheal GM-CSF administration. In the severe sepsis model, abdominal phagocyte function was greatly reduced as well and was restored by systemic IFNβ administration. However, this effect was not seen when prophylactic administration was given before sepsis.

Academic Significance and Societal Importance of the Research Achievements

敗血症は、いまだに死亡率が高く、確立された薬物療法が無い病態である。臨床試験で有効性が示せない理由の１つに、病態の不均一性が挙げられている。本研究は、動物モデルで、ヒトの腹膜炎敗血症の病態を再現し、一次免疫担当細胞の機能が抑制されていることを直接的に示したこと、また免疫賦活効果を示すサイトカインを投与し、実際に機能の復活と生存率の改善を観察できたことは、今後の治療につながる社会的意義が大きい成果であると考える。

Research Products

• [Journal Article] Post-surgical immune suppression: another target to improve postoperative outcomes (2019)
  • Author(s): Uchida K
  • Journal Title: J Anesth Volume: 33 Issue: 6 Pages: 625-627
  • DOI: 10.1007/s00540-019-02651-3
  • NAID: 40022092536
  • Peer Reviewed / Open Access
• [Journal Article] Reference value for expiratory time constant calculated from the maximal expiratory flow-volume curve. (2019)
  • Author(s): Ikeda T, Yamauchi Y, Uchida K, Oba K, Nagase T, Yamada Y.
  • Journal Title: BMC Pulm Med. Volume: 19 Issue: 1 Pages: 208-208
  • DOI: 10.1186/s12890-019-0976-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Assessment of Therapeutic Interventions and Lung Protective Ventilation in Patients With Moderate to Severe Acute Respiratory Distress Syndrome: A Systematic Review and Network Meta-analysis (2019)
  • Author(s): Aoyama H, Uchida K, Aoyama K, Pechlivanoglou P, Englesakis M, Yamada Y, Fan E.
  • Journal Title: JAMA Netw Open Volume: 2 Issue: 7 Pages: e198116-e198116
  • DOI: 10.1001/jamanetworkopen.2019.8116
  • Peer Reviewed / Open Access
• [Journal Article] Synergistic cytoprotection by co-treatment with dexamethasone and rapamycin against proinflammatory cytokine-induced alveolar epithelial cell injury. (2019)
  • Author(s): Kuwajima K, Chang K, Furuta A, Bougaki M, Uchida K, Sawamura S, Yamada Y.
  • Journal Title: J Intensive Care Volume: 7 Issue: 1 Pages: 12-12
  • DOI: 10.1186/s40560-019-0365-5
  • Peer Reviewed / Open Access
• [Journal Article] Early-phase Innate Immune Suppression in Murine Severe Sepsis Is Restored with Systemic Interferon-β (2018)
  • Author(s): Kusakabe Yoshiomi、Uchida Kanji、Yamamura Yoshiro、Hiruma Takahiro、Totsu Tokie、Tamai Yuho、Tsuyuzaki Hitoshi、Hasegawa Kyoko、Chang Kyungho、Yamada Yoshitsugu
  • Journal Title: Anesthesiology Volume: 129 Issue: 1 Pages: 131-142
  • DOI: 10.1097/aln.0000000000002185
  • Peer Reviewed
• [Journal Article] Interferon-β Improves Sepsis-related Alveolar Macrophage Dysfunction and Post-septic ARDS-related Mortality (2018)
  • Author(s): Hiruma Takahiro、Tsuyuzaki Hitoshi、Uchida Kanji、Trapnell Bruce C、Yamamura Yoshiro、Kusakabe Yoshiomi、Totsu Tokie、Suzuki Takuji、Morita Shigeki、Doi Kent、Noiri Eisei、Nakamura Kensuke、Nakajima Susumu、Yahagi Naoki、Morimura Naoto、Chang Kyungho、Yamada Yoshitsugu
  • Journal Title: American Journal of Respiratory Cell and Molecular Biology Volume: 印刷中 Issue: 1 Pages: 45-55
  • DOI: 10.1165/rcmb.2017-0261oc
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Effects of peritoneal polymicrobial infection on the maturation and function of alveolar macrophage and therapeutic effect of intratracheal GM-CSF (2019)
  • Author(s): Tsuyuzaki H, Hiruma T, Uchida K, Tamai Y, Yamada Y.
  • Organizer: American Thoracic Society International Conference 2019
  • Int'l Joint Research
• [Presentation] Effects of Peritoneal Polymicrobial Infection on Lung Innate Immunity and Therapeutic Effect of Intratracheal GM-CSF. (2018)
  • Author(s): Tsuyuzaki H, Uchida K, Hiruma T, Yamada Y.
  • Organizer: American Thoracic Society International Conference 2018
  • Int'l Joint Research