5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivative attenuates lupus nephritis with less effect to thymocyte development
| Autor: | Chuan Bai, Xuyan Tian, Huanpeng Chen, Fengjiao Wei, Zhonghua Liu, Xiaoqing Zhou, Bolan Yu, Zhaofeng Huang, Xixin He |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Thymoma
Immunology Lupus nephritis Apoptosis Kidney Antibodies Pathogenesis RAR-related orphan receptor gamma hemic and lymphatic diseases medicine Animals Lymph node Autoimmune disease Mice Inbred BALB C Thymocytes Terpenes Chemistry Cell Differentiation DNA Nuclear Receptor Subfamily 1 Group F Member 3 medicine.disease Lupus Nephritis Mice Inbred C57BL Thymocyte Pyrimidines medicine.anatomical_structure Cancer research Cytokines Th17 Cells Female Immunosuppressive Agents Spleen CD8 |
| Zdroj: | Immunologic Research. 69:378-390 |
| ISSN: | 1559-0755 0257-277X |
| DOI: | 10.1007/s12026-021-09204-5 |
| Popis: | Retinoic‑acid‑receptor‑related orphan nuclear hormone receptor gamma t (RORγt), a critical transcriptional factor of Th17 cells, is a potential therapeutic target for Th17-mediated autoimmune diseases. In addition, RORγt is essential for thymocyte survival and lymph node development, and RORγt inhibition or deficiency causes abnormal thymocyte development, thymus lymphoma, and lymph node defect. Recent study demonstrated that specific regulation of Th17 differentiation related to the hinge region of RORγt. In this research, we investigated the effect of RORγt inhibitor, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivative (TTP), in the therapy of lupus nephritis and its safety on thymocyte development. We demonstrated that TTP repressed the development of Th17 cells and ameliorated the autoimmune disease manifestation in the pristane-induced lupus nephritis mice model. The treatment of TTP in the mice did not interfere with thymocyte development, including total thymocyte number and proportion of CD4+CD8+ double-positive populations in the thymus, and had no substantial effects on the pathogenesis of thymoma. The TTP had a stronger affinity with full-length RORγt protein compared with the truncated RORγt LBD region via surface plasmon resonance, which indicated TTP binding to RORγt beyond LBD region. Molecular docking computation showed that the best binding pocket of TTP to RORγt is located in the hinge region of RORγt. In summary, as a RORγt inhibitor, TTP had a potential to develop the clinical medicine for treating Th17-mediated autoimmune diseases with low safety risk for thymocyte development. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink