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Research Labs: Moriya Tsuji, M.D., Ph.D.
CD1d/NKT-binding glycolipids as an adjuvant for T cell-based HIV and malaria vaccines The eradication of global pathogens responsible for endemic and pandemic diseases hinges upon the development of effective vaccines. This is certainly the case for HIV and malaria. However, our inability to elicit “strong and long-lasting” protective T cell responses, particularly CD8+ T cell responses, has been a major obstacle to successful vaccine development. Accordingly, adjuvant technologies will likely be critical not only to overcome pre-existing immunity to viral vaccine vectors but also to further enhance vaccine immunogenicity. Our previous studies have demonstrated that a CD1d molecule-binding, natural killer T (NKT) cell ligand, alpha-galactosylceramide (alpha-GalCer), can enhance protective CD8+ T cell responses elicited by HIV and malaria vaccines, including a DNA vaccine encoding HIV antigens and a recombinant adenovirus expressing a malarial antigen. In collaboration with two eminent chemistry groups directed by Dr. Chi-
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Huey Wong and Dr. Richard Franck, we have successfully identified several alpha-GalCer analogues that act as an NKT cell ligand. These include a synthetic C-glycoside analogue, alpha-C-GalCer (JEM in 2003 and PNAS in 2005), a sulfatide analogue, 3-O-sulfo-GalCer (PNAS in 2005), two bacterial glycosphingolipids, GSL-1A and GSL-1B, derived from Sphingomonas (Nature in 2005), and a diacylglycerol from Borrelia burgdorferi (Nature Immunology in 2006). Our most recent results indicate that introduction of a phenyl group at the end of eight fatty acid carbon chain yielded activities superior to alpha-GalCer (JACS in 2006). Thus, concrete clues on the structure-activity-relationship (SAR) are emerging from our preliminary studies on an initial library screening of glycolipids. We are continuing to screen a focused library of several hundreds alpha-GalCer analogues that we are generating, and selecting a smaller panel of candidate glycolipids based on their in vitro cytokine production profiles upon cultivation with murine and human NKT cells. We are also determining the in vivo cytokine production profiles elicited by the selected glycolipids upon administering them into mice. These in vitro and in vivo screening process will lead us to choose about a handful of promising candidate glycolipids that would display strong Th1-biased, Th2-biased, or bipolar activities. These glycolipids having a distinct biological activity will present us an opportunity to determine the means by which glycolipids elicit Th1 versus Th2 cytokine secretion, in collaboration with Dr. Mitchell Kronenberg at La Jolla Institute of Allergy & Immunology. Ultimately, we plan to determine the magnitude of adjuvant effect that each of these newly identified glycolipids contributes to the immunogenicity of HIV and malaria vaccines in a mouse model. 
