Novel glycolipids in CD1d-mediated immunity: synthesis of new agonists of CD1d

Abstract

The glycolipid α-galactosyl ceramide, α-GalCer, has been shown to stimulate the proliferation of murine spleen cells and activate the immune system. Stimulation occurs through binding of the glycolipid to the protein CD1d. Subsequent presentation of the CD1d−glycolipid complex to invariant Natural Killer T cells (iNKT cells) initiates the proliferation of a host of cytokines leading to an immune response The therapeutic potential of α-GalCer is currently being explored; however the induction of both Th1 and Th2 cytokines by this agent is likely to limit its therapeutic application. Significantly, analogues of α-GalCer have been shown to induce iNKT cell-derived cytokines more selectively through a skewed Th1-Th2 response. To date, very few alterations around the amide bond have been explored. To investigate its importance in iNKT cell stimulation, a range of α-GalCer and threitol ceramide (ThrCer) analogues has been synthesised in which the amide functionality in these two leads has been replaced with different carbonyl functional groups. These compounds have been tested for iNKT cell induction and in particular their Th1/Th2 response, which determined their therapeutic potential. Labelled derivatives of α-GalCer and ThrCer have also been designed and synthesised to find application in lipid trafficking studies.