The role of inflammasome in steroid refractory graft-versus-host disease after allogeneic stem cell transplantation

• Project/Area Number: 20K08704
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Yamagata University
• Principal Investigator: TOUBAI TOMOMI 山形大学, 医学部, 講師 (40802111)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 移植片対宿主病 / ステロイド不応移植片対宿主病 / NLRP6 / アロ免疫 / T細胞活性化シグナリング / 同種造血細胞移植 / 同種造血幹細胞移植 / ステロイド抵抗性 / メタボライト / T細胞 / インフラマゾーム

Outline of Research at the Start

同種造血幹細胞移植は造血器腫瘍に対する根治療法であるが、重篤な合併症の一つに移植片対宿主病（graft-versus-host disease: GVHD）があり、特に第一選択薬の副腎皮質ステロイドホルモン（ステロイド）に抵抗性を有する、ステロイド不応・抵抗性GVHD (steroid refractory/resistant GVHD: SR-GVHD)の予後は極めて不良である。本研究では、炎症反応に重要な役割を示すインフラマゾームの一種、NOD-like receptor family pyrin domain containing 6 (NLRP6)のステロイド抵抗性に与える影響をマウス骨髄移植モデルを用いて検討し、SR-GVHDの発症機序を明らかにし、標準療法確立の礎とすることを目的とする。

Outline of Final Research Achievements

The outcome of steroid refractory GVHD (SR-GVHD) is poor due to a lack of effective treatments. To find mechanisms of SR-GVHD, we have investigated fecal metabolome analyses using a murine bone marrow transplantation (BMT) and found several metabolites were altered in the allogeneic group. Next, we focused on the role of NLRP6 in donor T cells for the development of GVHD. To determine if NLRP6 influences donor T cell responses, we used multiple BMT models and found that the survival of allogeneic recipients of Nlrp6-/- donor T cells was significantly worse than those receiving WT-B6 T cells. To find mechanisms, we tested various T cell activation signaling pathways and found enhanced signaling, particularly for ZAP-70, in Nlrp6-/- T cells. These data suggested that NLRP6 in donor T cells may regulate allogeneic immune responses via a ZAP-70 pathway. Overall, our data suggest that controlling NLRP6 expression in T cells may be a novel way to decrease acute GVHD.

Academic Significance and Societal Importance of the Research Achievements

本研究成果から、同種移植後には特定の腸内細菌メタボライトが著しく変動することで、標的臓器における組織修復及び恒常性の維持機構に変化をもたらしている可能性が示唆された。一方、活性化T細胞におけるNLRP6-ZAP70-Erk免疫抑制機構は、新たな免疫チェックポイントとなる可能性があることから、今後のSR-GVHD発症メカニズムの鍵となる可能性が示唆された。

Research Products

• [Int'l Joint Research] ミシガン大学/インディアナ大学(米国)
• [Journal Article] How does transfusion-associated graft-versus-host disease compare to hematopoietic cell transplantation-associated graft-versus-host disease? (2022)
  • Author(s): Aizawa Keiko、Peltier Daniel、Matsuki Eri、Toubai Tomomi
  • Journal Title: Transfusion and Apheresis Science Volume: 61 Issue: 2 Pages: 103405-103405
  • DOI: 10.1016/j.transci.2022.103405
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] GPR109A in GVHD: friend or foe? (2022)
  • Author(s): Toubai Tomomi
  • Journal Title: Blood Volume: 139 Issue: 15 Pages: 2271-2272
  • DOI: 10.1182/blood.2021014128
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Editorial on Translational Research in Graft-Versus-Host Disease (GVHD) and Graft-Versus-Tumor (GVT) Effect After Allogeneic Hematopoietic Cell Transplantation (2022)
  • Author(s): Czech Marie、Zeiser Robert、Toubai Tomomi
  • Journal Title: Frontiers in Immunology Volume: 13 Pages: 1-2
  • DOI: 10.3389/fimmu.2022.948720
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Successful treatment of acute pancreatitis associated with late-onset acute liver GVHD after second allogeneic hematopoietic cell transplantation (2022)
  • Author(s): Hosokawa Yuka、Toubai Tomomi、Ohe Rintaro、Hosokawa Masashi、Sato Ryo、Yamada Akane、Aizawa Keiko、Himuro Masahito、Ito Satoshi、Yamamoto Masakazu、Peltier Daniel、Ishizawa Kenichi
  • Journal Title: Blood Cell Therapy Volume: 5 Issue: 3 Pages: 79-82
  • DOI: 10.31547/bct-2021-023
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fecal metabolomic profiles in experimental murine bone marrow transplantation (2022)
  • Author(s): 関口恵理華,東梅友美,須藤将裕,松木絵理,宮田匡大,石澤 賢一
  • Journal Title: Rinsho Ketsueki Volume: 63 Issue: 1 Pages: 37-44
  • DOI: 10.11406/rinketsu.63.37
  • NAID: 130008158336
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed / Open Access
• [Journal Article] 同種造血幹細胞移植後のステロイド不応性GVHDのメカニズムに関する最新の知見. (2021)
  • Author(s): 東梅友美,鳥居由佳
  • Journal Title: 炎症と免疫 Volume: 29 Pages: 57-62
• [Journal Article] ステロイド抵抗性GVHDの病態と治療 (2021)
  • Author(s): 東梅友美,鳥居由佳
  • Journal Title: 血液内科 Volume: 82 Pages: 388-393
  • NAID: 40022514297
• [Journal Article] ステロイド抵抗性GVHDの病態,診断,治療 (2021)
  • Author(s): 東梅友美,鳥居由佳
  • Journal Title: 臨床血液 Volume: 62 Pages: 1567-1577
  • NAID: 130008124406
  • Peer Reviewed / Open Access
• [Journal Article] Immunopathology and biology-based treatment of steroid-refractory graft-versus-host disease (2020)
  • Author(s): Toubai Tomomi、Magenau John
  • Journal Title: Blood Volume: 136 Issue: 4 Pages: 429-440
  • DOI: 10.1182/blood.2019000953
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Biology based novel treatment approaches of GVHD (2022)
  • Author(s): Tomomi Toubai
  • Organizer: The International Congress of BMT 2022
  • Int'l Joint Research / Invited
• [Presentation] Recent advances of pathophysiology of acute graft-versus-host disease-2022 (2022)
  • Author(s): Tomomi Toubai
  • Organizer: KSEH spring E-symposium
  • Int'l Joint Research / Invited
• [Presentation] NLRP6-ZAP-70 pathway regulates Donor T cell activation in GVHD (2022)
  • Author(s): Matsuki E, Suto M, Miyata M, Hosokawa Y, Tamaki H, Tawara I, Peltier D, Chen G, Ishizawa K, Reddy P, Toubai T.
  • Organizer: 2023 Transplantation & Cellular Therapy Meetings
  • Int'l Joint Research
• [Presentation] NLRP6 Regulates Allogeneic Donor T Cells. (2022)
  • Author(s): Suto M, Matsuki E, Miyata M, Sekiguchi E, Tamaki H, Tawara I, Peltier D, Chen G, Ishizawa K, Reddy P, Toubai T
  • Organizer: 2022 Transplantation & Cellular Therapy Meetings
  • Int'l Joint Research
• [Presentation] 当院における初回同種造血幹細胞移植症例のEASIXを用いた予後予測の後方視解析 (2022)
  • Author(s): 細川由佳,東梅友美,大谷幸一,石澤悠樹,長野裕祐,高橋諒,佐藤諒,細川雅司,渡邊正太郎,山田茜,鈴 木琢磨,相澤桂子,伊藤巧,石澤賢一
  • Organizer: 第45回日本造血・免疫細胞療法学会総会
• [Presentation] NLRP6-ZAP70 pathway regulates donor T cell activation in GVHD (2022)
  • Author(s): 松木絵理,須藤将裕,宮田匡大,細川由佳,玉置広哉,俵功,Daniel Peltier, Grace Chen,石澤賢一, Pavan Reddy,東梅友美
  • Organizer: 第45回日本造血・免疫細胞療法学会総会
• [Presentation] NLRP6 regulates allogeneic donor T cell responses (2022)
  • Author(s): 松木絵理,須藤将裕,宮田匡大,関口恵理華,玉置広哉,俵功,Daniel Peltier, Grace Chen,石澤賢一, Pavan Reddy,東梅友美
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] NLRP6はドナーT細胞の活性化を制御する (2022)
  • Author(s): 松木絵理,須藤将裕,宮田匡大,関口恵理華,玉置広哉,俵功,Daniel Peltier, Grace Chen,石澤賢一,東梅友美, Pavan Reddy
  • Organizer: 第44回日本造血・免疫細胞療法学会総会
• [Presentation] NLRP6 Regulates Allogeneic Donor T Cells. (2022)
  • Author(s): Suto M, Matsuki E, Miyata M, Sekiguchi E, Tamaki H, Tawara I, Peltier D, Chen G, Ishizawa K, Reddy P, Toubai T.
  • Organizer: 2022 Transplantation & Cellular Therapy Meetings
  • Int'l Joint Research
• [Presentation] マウス骨髄移植モデルにおける糞便中メタボライト解析 (2021)
  • Author(s): 関口恵理華,東梅友美,須藤将裕,松木絵里,宮田匡大,市川翼,佐藤諒,細川雅司,柳谷稜,山田茜,相澤桂子,氷室真仁,伊藤巧,山本雅一,石澤賢一
  • Organizer: 第131回日本血液学会東北地方会
• [Presentation] NLRP6-deficient T cells exacerbate GVHD (2021)
  • Author(s): 須藤将裕,松木絵理,宮田匡大,関口恵理華,石澤賢一,東梅友美
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] The Absence of NLRP6 in Donor T Cells Exacerbates Gvhd (2021)
  • Author(s): Suto M, Matsuki E, Miyata M, Sekiguchi E, Tamaki H, Tawara I, Peltier D, Chen G, Ishizawa K, Reddy P, Toubai T.
  • Organizer: 63rd Annual Meeting of American Society of Hematology (ASH)
  • Int'l Joint Research