NKT Cell-Stimulating Synthetic Glycolipids as Potential Therapeutics for Autoimmune Disease

Takashi      Yamamura; Katsuichi      Miyamoto; Zsolt      Illes; Endre      Pal; Manabu      Araki; Sachiko      Miyake

Abstract

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 α-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 α-galactosylceramide (α-GalCer) derived from marine sponges. α-GalCer exhibits significant immunomodulatory effects by stimulating NKT cells. However, we found that an altered analogue of α-GalCer with a shorter sphingosine chain (OCH), is more useful than α-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 α-GalCer appear to be promising reagents for treatment of human autoimmune diseases.

Keywords: NKT Cell-Stimulating Synthetic Glycolipids, sphingosine, autoimmunity

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