Synthetic Glycolipid Ligands for Human iNKT Cells as Potential Therapeutic Agents for Immunotherapy

Invariant natural killer T (iNKT) cells are an attractive therapeutic target in autoimmune diseases, since they play a major role in immune regulation. iNKT cells recognize glycolipid antigens presented by CD1d molecules that resemble the non-polymorphic MHC class I protein. α-galactosylceramide (α-GalCer) isolated from marine sponge has long been used as a prototype iNKT cell ligand in the laboratory. As α-GalCer is the most efficacious ligand for iNKT cells, its potential to treat autoimmune disease has been evaluated in animal models. Previous studies showed that α- GalCer effectively suppressed disease in some autoimmunity models, but not in others. This inconsistency may be attributed to the ability of α-GalCer to induce the production of both proinflammatory Th1 and anti-inflammatory Th2 cytokines by iNKT cells. To overcome this issue, we and other groups have synthesized new, unnatural glycolipids by modifying the structure of α-GalCer. These efforts have led to an identification of glycolipid compounds that provoke the production of Th2 (but not Th1) cytokines by iNKT cells. Among these novel ligands, an α-GalCer analogue named OCH, which contains a truncated sphingosine chain, induces a Th2 biased response by murine iNKT cells. Here we describe that OCH also polarizes human iNKT cells towards Th2, which opens up a new avenue for the clinical application of glycolipid compounds in treating of autoimmune diseases such as multiple sclerosis. The pursuit of synthetic glycolipid antigens has the great potential to lead to a better understanding of the regulatory effects of human iNKT cells and development of a new therapeutic agent for autoimmune diseases.