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.

Aim

To determine the effects of synthetic GSL structures on their immune modulatory functions.

Methods

GSLs of various structures were tested in vitro and in an animal model of Concanavalin A (ConA) immune-mediated hepatitis.

Results

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.

Summary

The assembly of GSLs determines their immunomodulatory effect and can serve as a method for structure-based design of immunotherapy.

中文翻译：

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糖鞘脂的组装决定了它们的免疫调节作用：一种基于结构的免疫疗法设计的新方法。

构效关系提供了对β-糖鞘脂（GSLs）与TCR和CD1d分子的结合相互作用的见解，以及随后调节性NKT细胞的免疫应答。

目标

确定合成的GSL结构对其免疫调节功能的影响。

方法

在体外和伴刀豆球蛋白A（ConA）免疫介导的肝炎动物模型中测试了各种结构的GSL 。

结果

在体外，使用SV40结合活猴CV1细胞中，升-苏C8-β-LacCer抑制的立体异构体小窝内化，降低病毒结合到细胞表面。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，可以抑制免疫介导的肝炎并降低剂量依赖性的IFNγ水平方式。LR172和LR178的有益作用与肝细胞凋亡的抑制，肝中磷酸化STAT3表达的增加以及NKT肝/脾比例的增加有关。

概要

GSL的组装决定了它们的免疫调节作用，可作为基于结构的免疫疗法设计方法。