NKT cell-stimulating synthetic glycolipids as potential therapeutics for autoimmune disease.

Although T cells were previously believed to recognize only peptide antigen associated with the major histocompatibility complex (MHC), recent studies have shown that there are unique T cells specialized for recognition of lipid or glycolipid antigens bound to the MHC class I-like CD1 molecules (CD1a, b, c or d). Among these lipid-specific T cells, CD1d-restricted T cells, also referred to as natural killer (NK) T cells, are of special interest as a target of drug development, since their role in immunoregulation has been indicated in various physiological or disease conditions including autoimmunity. They are unique in their homogeneous ligand specificity for alpha-glycosylated sphingolipid and secrete large amounts of regulatory cytokines shortly after T cell receptor (TCR) engagement. The first glycolipid identified as an NKT cell ligand was alpha-galactosylceramide (alpha-GalCer) derived from marine sponges. alpha-GalCer exhibits significant immunomodulatory effects by stimulating NKT cells. However, we found that an altered analogue of alpha-GalCer with a shorter sphingosine chain (OCH), is more useful than alpha-GalCer for treatment of autoimmune disease models, because of its ability to selectively induce IL-4, a key cytokine for control of autoimmunity. As such, altered glycolipid ligands (AGL) of alpha-GalCer appear to be promising reagents for treatment of human autoimmune diseases.