Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Department of Chemistry & Biochemistry, Queens College of the City University of New York, United States; Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram 695019, Kerala, India.
Cell Immunol. 2020 Sep;355:104157. doi: 10.1016/j.cellimm.2020.104157. Epub 2020 Jul 3.
Structure-activity relationships provide insight into the binding interactions of beta-glycosphingolipids (GSLs) with both the TCR and the CD1d molecules, as well as the subsequent immunologic response of regulatory NKT cells.
To determine the effects of synthetic GSL structures on their immune modulatory functions.
GSLs of various structures were tested in vitro and in an animal model of Concanavalin A (ConA) immune-mediated hepatitis.
In vitro, using SV40 binding to live monkey CV1 cells, the l-threo stereoisomer of C8-β-LacCer inhibits caveolar internalization, reducing viral binding to the cell surface. In vivo, in the ConA model, LR172, which has a saturated C8 chain, and LR178, which has a trans double bond at C-2 in the C8 chain, suppressed the immune-mediated liver inflammation and reduced IFNγ levels in a dose dependent manner. The beneficial effects of LR172 and of LR178 are associated with suppression of liver apoptosis, increased phosphorylated STAT3 expression in the liver, and an increase in the NKT liver/spleen ratio.
The assembly of GSLs determines their immunomodulatory effect and can serve as a method for structure-based design of immunotherapy.
结构-活性关系提供了深入了解β-糖鞘脂（GSL）与 TCR 和 CD1d 分子结合相互作用的信息，以及调节性自然杀伤 T（NKT）细胞的后续免疫反应。
确定合成 GSL 结构对其免疫调节功能的影响。
在体外和 ConA 免疫介导的肝炎动物模型中测试了各种结构的 GSL。
在体外，使用 SV40 与活猴 CV1 细胞结合，C8-β-LacCer 的 l-苏型异构体抑制小窝内陷，减少病毒与细胞表面的结合。在体内，在 ConA 模型中，具有饱和 C8 链的 LR172 和在 C8 链的 C-2 处具有反式双键的 LR178 以剂量依赖的方式抑制免疫介导的肝炎症并降低 IFNγ 水平。LR172 和 LR178 的有益作用与抑制肝凋亡、增加肝中磷酸化 STAT3 表达以及增加 NKT 肝/脾比有关。
GSL 的组装决定了它们的免疫调节作用，可以作为基于结构的免疫疗法设计的方法。
