The mechanism of induction of regulatory cells involved in suppression of autoimmune diseases

• Project/Area Number: 19K16682
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: SHIMOKAWA Chikako 国立感染症研究所, 寄生動物部, 室長 (60708569)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 衛生仮説 / 自己免疫疾患 / 寄生虫 / 免疫抑制 / 腸内細菌叢 / 免疫 / 腸内細菌 / 一型糖尿病 / 感染免疫学 / 免疫学

Outline of Research at the Start

申請者らはこれまでに腸管寄生蠕虫が誘導するCD8陽性制御性T細胞(CD8Treg)が自己免疫疾患である1型糖尿病(T1D)の発症を抑制することを見出している。一方でCD8Tregは寄生虫感染によってしか誘導されないにもかかわらず寄生虫 がどうやって誘導するのか、その誘導メカニズムは明らかとなっていない。本研究では腸管寄生蠕虫によるCD8Tregの誘導メカニズムをCD8Tregの誘導に関わる腸内細菌、寄生虫由来の腸内代謝産物を網羅的に解析し、誘導との関係を探索する。さらには、CD8TregとT1Dの関連性を一般化するためにT1D患者での臨床的アプローチも試みる。

Outline of Final Research Achievements

Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing pancreatic β-cells are destroyed. Intestinal helminths can cause asymptomatic chronic and immunosuppressive infections and suppress disease in rodent models of T1D. However, the underlying regulatory mechanisms for this protection are unclear. Here, we report that CD8+ regulatory T (Treg) cells prevent the onset of streptozotocin -induced diabetes by a rodent intestinal nematode. Trehalose derived from nematodes affects the intestinal microbiota and increases the abundance of Ruminococcus spp., resulting in the induction of CD8+ Treg cells.

Academic Significance and Societal Importance of the Research Achievements

申請者らが独自に確立したHpによるCD8陽性制御性T細胞の誘導を介した自己免疫の抑制モデルは独創的であり、腸内環境の解析もこれまで報告のない新規性の高い研究である。また、免疫抑制を誘導できる寄生虫由来の物質が特定できれば、新規の免疫調節機能を持つ生物製剤としての可能性を秘めており、炎症性疾患の治療へとつながることが期待される。さらには、シームレスな臨床応用を見据えT1D患者のCD8Tregを中心に免疫学的、腸内細菌学的に解析を行なった点も先駆的である。このように寄生虫と抑制性の免疫系の相互作用を明らかにすることは広くライフサイエンスの向上に寄与できると確信している。

Research Products

• [Journal Article] The impact of the gut microbiome on extra-intestinal autoimmune diseases (2023)
  • Author(s): Eiji Miyauchi ,Chikako Shimokawa , Alex Steimle , Mahesh S Desai , Hiroshi Ohno
  • Journal Title: Nat Rev Immunol . Volume: 1 Issue: 1 Pages: 9-23
  • DOI: 10.1038/s41577-022-00727-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Human gut microbiota and its metabolites impact immune responses in COVID-19 and its complications (2022)
  • Author(s): Nagata N, Takeuchi T, Masuoka H, Aoki R, Ishikane M, Iwamoto N, Sugiyama M, Suda W, Nakanishi Y, Terada-Hirashima J, Kimura M, Nishijima T, Inooka H, Miyoshi-Akiyama T, Kojima Y, Shimokawa C, Hisaeda H, Zhang F, Yeoh YK, Ng SC, Uemura N, Itoi T, Mizokami M, Kawai T, Sugiyama H, Ohmagari N, Ohno H.
  • Journal Title: Gastroenterology Volume: 164 Issue: 2 Pages: 272-288
  • DOI: 10.1053/j.gastro.2022.09.024
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Assessment of SARS-CoV-2 infectivity of upper respiratory specimens from COVID-19 patients by virus isolation using VeroE6/TMPRSS2 cells. (2021)
  • Author(s): Ymada S, Fukushi S, Kinoshita H, Ohnishi M, Suzuki T, Fujimoto T, Saijo M, Maeda K; Virus Diagnosis Froup (NIID Toyama)
  • Journal Title: BMJ Open Respir Res Volume: 1
  • Peer Reviewed
• [Journal Article] Queuine is a nutritional regulator of Entamoeba histolytica response to oxidative stress and a virulence attenuator. (2021)
  • Author(s): Nagaraja S, Cai MW, Sun J, Varet H, Sarid L, Trebicz-GeffenM, Shaulov Y, Mazumdar M, Lagendre R, Coppee JY, Begley TJ, Dedon PC, Gourinath S, Guillen N, Saito-Nakano Y, Shimokawa C, Hisaeda H, Ankri S
  • Journal Title: mBio Volume: 12 Issue: 2
  • DOI: 10.1128/mbio.03549-20
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Long-term acrylamide exposure exacerbates brain and lung pathology in a mouse malaria model. (2021)
  • Author(s): Ngo-Thanh H, Thuy TD, Suzue K, Kamitani W, Yokoo H, Isoda K, Shimokawa C, Hisaeda H, Imai T.
  • Journal Title: Food Chem Toxicol Volume: 151 Pages: 112132-112132
  • DOI: 10.1016/j.fct.2021.112132
  • Peer Reviewed
• [Journal Article] Blood cerebrospinal fluid barrier: another site disrupted during experimental cerebral malaria caused by Plasmodium berghei ANKA (2020)
  • Author(s): Ngo-Thanh Ha、Sasaki Tsutomu、Suzue Kazutomo、Yokoo Hideaki、Isoda Koji、Kamitani Wataru、Shimokawa Chikako、Hisaeda Hajime、Imai Takashi
  • Journal Title: International Journal for Parasitology Volume: 50 Issue: 14 Pages: 1167-1175
  • DOI: 10.1016/j.ijpara.2020.07.007
  • Peer Reviewed
• [Journal Article] Potential and limitations of cross-protective vaccine against malaria by blood-stage naturally attenuated parasites (2020)
  • Author(s): Imai T, Suzue K, Ngo-Thanh H, Shimokawa C, Hisaeda H
  • Journal Title: Vaccines Volume: 8 Issue: 3 Pages: 375-375
  • DOI: 10.3390/vaccines8030375
  • Peer Reviewed / Open Access
• [Journal Article] IL-33 is essential to prevent high fat diet-induced obesity in mice infected with an intestinal helminth (2020)
  • Author(s): Obi S, Shimokawa C, Katsuura M, et al.
  • Journal Title: Parasite Immunol. Volume: e12700 Issue: 9
  • DOI: 10.1111/pim.12700
  • Peer Reviewed
• [Journal Article] CD8+ regulatory T cells are critical in prevention of autoimmune-mediated diabetes (2020)
  • Author(s): 3.Shimokawa C, Kato T, Takeuchi T, Ohshima N, Furuki T, Ohtsu Y, Suzue K, Imai T, Obi S, Olia A, Izumi T, Sakurai M, Arakawa H, Ohno H, Hisaeda H
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 1922-1922
  • DOI: 10.1038/s41467-020-15857-x
  • Peer Reviewed / Open Access
• [Journal Article] Suppression of systemic lupus erythematosus in NZBWF1 mice infected with Hymenolepis microstoma. (2020)
  • Author(s): OLIA A, SHIMOKAWA C, IMAI T, SUZUE K, HISAEDA H.
  • Journal Title: Parasitology International. Volume: 76 Pages: 102057-102057
  • DOI: 10.1016/j.parint.2020.102057
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Fluctuations of Spleen Cytokine and Blood Lactate, Importance of Cellular Immunity in Host Defense Against Blood Stage Malaria Plasmodium yoelii. (2019)
  • Author(s): Imai T, Suzue K, Ngo-Thanh H, et al.
  • Journal Title: Front Immunol. Volume: 10:2207.
  • DOI: 10.3389/fimmu.2019.02207
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Suppression of obesity by an intestinal helminth through interactions with intestinal microbiota. (2019)
  • Author(s): Shimokawa C, Obi S, Shibata M, Olia A, Imai T, Suzue K, Hisaeda H.
  • Journal Title: Infection and Immunity Volume: 印刷中 Issue: 6
  • DOI: 10.1128/iai.00042-19
  • Peer Reviewed / Open Access
• [Presentation] Microbiota-derived acetic acid suppresses Type 1 diabetes via G-protein-coupled receptor on CD8+ Tregs (2022)
  • Author(s): Chikako Shimokawa, Hajime Hisaeda
  • Organizer: Immunology 2022
  • Int'l Joint Research
• [Presentation] アニサキス特異的なIgEは胃内細菌によって誘導される (2022)
  • Author(s): 下川周子, 竹内直志, 加藤完, 杉山広, 大野博司, 久枝一
  • Organizer: 第91回日本寄生虫学会学術集会
• [Presentation] Anisakis-specific IgE is induced by gastric bacteria (2022)
  • Author(s): Chikako Shimokawa, Tamotsu Kato, Tadashi Takeuchi, Hiroshi Ohno, Hajime Hisaeda
  • Organizer: 第14回日本寄生虫免疫研究会
• [Presentation] Intestinal microbiota in mice infected with helminth suppress Type 1 Diabetes by inducing CD8+ Tregs via production of acetic acid. (2021)
  • Author(s): Shimokawa C, Takeuchi T, Kato T, Kanaya T, Ohno H, Hisaeda H
  • Organizer: 日本寄生虫学会
• [Presentation] Helminth-Microbiota crosstalk suppresses type 1 diabetes mice via induction of CD8+ Treg (2021)
  • Author(s): Shimokawa C and Hisaeda H
  • Organizer: 第19回あわじ感染と免疫国際フォーラム
  • Int'l Joint Research
• [Presentation] 寄生虫感染によって誘導された腸内細菌はCD8Tregを増殖させることで1型糖尿病を抑制する (2021)
  • Author(s): 下川周子
  • Organizer: 第７回Gut microbiota 研究会
  • Invited
• [Presentation] Microbiota-derived acetic acid suppresses Type 1 diabetes via a G-protein-coupled receptor on CD8+ Tregs (2021)
  • Author(s): Shimokawa C, Takeuchi T, Kato T, Kanaya T, Ohno H, Hisaeda H.
  • Organizer: 第50回日本免疫学会
• [Presentation] CD8+ regulatory T cells play a critical role in prevention of autoimmune-mediated diabetes (2020)
  • Author(s): Chikako Shimokawa, Tamotsu Kato, Tadashi Takeuchi, Hiroshi Ohno, Hajime Hisaeda
  • Organizer: 第89回日本寄生虫学会学術集会
• [Presentation] Trehalose produced from parasites induces regulatory T cells to suppress autoimmune diseases (2020)
  • Author(s): Chikako Shimokawa, Tamotsu Kato, Tadashi Takeuchi, Hiroshi Ohno, Hajime Hisaeda.
  • Organizer: 第13回寄生虫免疫研究会
• [Presentation] CD8+ regulatory T cells play a critical role in prevention of autoimmune-mediated diabetes (2020)
  • Author(s): Chikako Shimokawa, Tamotsu Kato, Tadashi Takeuchi, Hiroshi Ohno, Hajime Hisaeda.
  • Organizer: 第13回寄生虫免疫研究会
• [Presentation] Trehalose from parasitic worm prevents type 1 diabetes by communicating with gut microbes (2019)
  • Author(s): Chikako Shimokawa, Tamotsu Kato, Tadashi Takeuchi, Hiroshi Ohno, Hajime Hisaeda.
  • Organizer: Keystone symposia Helminths,
  • Int'l Joint Research
• [Presentation] Prevention of drug-induced systemic sclerosis in mice infected with intestinal helminthes (2019)
  • Author(s): Akiko Sekiguchi, Sei-ichiro Motegi, Osamu Ishikawa, Chikako Shimokawa, Hajime Hisaeda
  • Organizer: The 47th European Society for Dermatological Research (ESDR) Annual Meeting
  • Int'l Joint Research
• [Presentation] CD8+ regulatory T cells play a critical role in prevention of type 1 diabetes (2019)
  • Author(s): Chikako Shimokawa, Tamotsu Kato, Tadashi Takeuchi, Hiroshi Ohno, Hajime Hisaeda.
  • Organizer: 第18回あわじしま感染症・免疫フォーラム
  • Int'l Joint Research
• [Book] 自己免疫疾患としての1型糖尿病と腸内細菌との関連, 実験医学 (2019)
  • Author(s): 下川周子
  • Total Pages: 6
  • Publisher: 羊土社
• [Book] 腸管寄生虫と腸内細菌のクロストークによる1 型糖尿病抑制メカニズム, 臨床免疫・アレルギー科 (2019)
  • Author(s): 下川周子、久枝一
  • Total Pages: 6
  • Publisher: 科学評論社