Development of novel therapies targeting pathogenic plasmablasts in SLE based on gene expression of B cell subsets

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08452
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Tohoku University
• Principal Investigator: Fujii Hiroshi 東北大学, 大学病院, 准教授 (30531321)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 全身性エリテマトーデス / 形質芽細胞

Outline of Final Research Achievements

The purpose of this study is to develop a treatment that specifically targets the plasmablasts in systemic lupus erythematosus (SLE) by comparing the differentially expressed genes in peripheral blood plasmablasts between SLE patients and healthy individuals with those in a B-cell culture system, and by identifying drugs that target these genes. We attempted to establish induction systems for pathogenic and non-pathogenic B cells from naive B cells to examine characteristic gene expression in pathogenic B cells, and searched for selective treatments in the pathogenic B cell stimulation system using various inhibitors. In the pathogenic B cell stimulation system, the inhibitor TAK-931, which specifically targets CDC7-an enzyme that was found to be upregulated specifically in SLE plasma cells in in vivo microarray studies-showed a strong tendency to suppress differentiation to plasmablasts.

Free Research Field

膠原病学

Academic Significance and Societal Importance of the Research Achievements

ナイーブB細胞から非病原性B細胞の誘導系の樹立を試みた。培養開始後、適切なタイミングでIL-2, IL-6, IL-10,IL-21を加えることでTLRリガンドを用いずに形質芽細胞を誘導する系を樹立することに成功した。本系を用いて各種阻害剤による分化、分裂の阻害効果を検証した。CDC7の阻害薬により病原性、非病原性B細胞刺激において、共に形質芽細胞への分化抑制が認められ、病原性B細胞刺激においてより強く抑制される傾向が認められた。CDC7の阻害剤がSLEの病原性B細胞特異的な治療薬になる可能性が示され、加えて本培養系が病原性B細胞特異的な薬剤のスクリーニングの系となりうる。