Induction of Immune tolerance in the intestine depending on metabolic checkpoint

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H02904
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Okayama University
• Principal Investigator: Fujiwara Hideaki 岡山大学, 大学病院, 研究准教授 (90743683)
• Co-Investigator(Kenkyū-buntansha): 藤井 伸治 岡山大学, 大学病院, 准教授 (60362977) ; 前田 嘉信 岡山大学, 医歯薬学域, 教授 (60403474) ; 西森 久和 岡山大学, 医学部, 客員研究員 (70756064)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: GVHD / 腸管上皮細胞 / ミトコンドリア

Outline of Final Research Achievements

We investigated the metabolic dynamics of intestinal epithelial cells in intestinal GVHD, a serious complication after allogeneic hematopoietic cell transplantation (allograft-versus-host disease (GVHD)), which is a disorder of the intestinal microbiota and a serious transplant complication. We found that intestinal epithelial cell injury by allogeneic reactive T cells causes specific mitochondrial complex II injury, which is exacerbated by drug-induced mitochondrial inhibition and genetic inhibition using the VillCre-Sdha flox mouse model of GVHD. The pathophysiology of GVHD is that the loss of homeostasis caused by energy deficiency due to mitochondrial dysfunction is the cause of tissue damage due to GVHD, and that increased oxygen concentration in the intestinal tract due to impaired oxygen utilization is the cause of disruption of the intestinal microbiota.

Free Research Field

造血細胞移植

Academic Significance and Societal Importance of the Research Achievements

同種造血幹細胞移植の腸管組織傷害ではドナーT細胞が腸管上皮細胞を標的とした傷害、特にミトコンドリア傷害が組織恒常性と腸内細菌叢の破綻・細菌由来代謝物の異常によるものであることを明らかにしてきた。これら恒常性破綻・腸内細菌叢の破綻とそれに伴う代謝物異常による組織代謝異常が、ミトコンドリア特異的傷害に由来していることから、免疫細胞を抑制せずにミトコンドリアを標的とした新たな治療開発への展開の可能性を見出し今後の発展が期待される。