Abstract:
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. A
im: 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-beta-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 IFN gamma 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.
