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

2022 Fiscal Year Final Research Report

• 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
• 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

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.

Free Research Field

同種造血細胞移植、移植片対宿主病、血液内科学

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。