Elucidation of the effect of S1PR2 on the disease specificity and pathophysiology of primary biliary cholangitis and its application to therapy

• Project/Area Number: 17K09458
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: Kawata Kazuhito 浜松医科大学, 医学部附属病院, 助教 (90722968)
• Co-Investigator(Kenkyū-buntansha): 小林 良正 浜松医科大学, 医学部, 助教 (50252185) ; 則武 秀尚 浜松医科大学, 医学部, 助教 (10467235)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 原発性胆汁性胆管炎 / S1PR2 / PBC / JTE / 慢性肝疾患 / 胆道学

Outline of Final Research Achievements

We compared the expression of Sphingosine-1-phosphate receptor 2(S1PR2) in liver biopsy samples from chronic liver diseases including Hepatitis B, Hepatitis C, autoimmune hepatitis, non-alcoholic liver disease, and primary biliary cholangitis using immunohistochemistry. As a result, there was no difference of S1PR2 expression in intrahepatic cholangiocytes between PBC and other chronic liver diseases.
We could reveal that JTE, an S1PR2 antagonist, suppressed LPS-induced CX3CL1 and CCL2 production in cholangiocytes via phosphorylation of STAT-1T cells, and then reduced T cells migration ability. Accordingly, an S1PR2 antagonist might have the potential to be a new therapeutic reagent.

Academic Significance and Societal Importance of the Research Achievements

原発性胆汁性胆管炎の唯一の保険適応のある治療薬はウルソデオキシコール酸であるが、無効例が約30％存在し、無効例に対する確立した治療薬は未だに無い。さらに進行例に対する有効な治療法は肝移植のみである。その様な状況下で、Sphingosine-1-phosphate receptor 2に対する拮抗薬が胆管細胞からのケモカイン産生を抑制し、単核球の遊走能を低下させて胆管炎を改善させる可能性を見出せた。原発性胆汁性胆管炎に対する有益な治療法が認められない中、今回の結果は新規治療薬創設へ繋がる貴重な結果と思われる。