title: Synthesis and evaluation of an alpha-C-galactosylceramide analogue that induces Th1-biased responses in human natural killer T cells.
abstract: An alpha-galactosylceramide (alphaGalCer, 1) and its isosteric C-glycoside analogue (2) were found to possess promising immunostimulatory activity because of their ability to activate natural killer T (NKT) cells. We report the synthesis of compound 3, a truncated nonisosteric C-alphaGalCer analogue, that like 2 is not enzymatically labile at the glycosidic linkage, but has the anomeric carbon directly bonded to the C1 of the phytoceramide backbone. We compared the biological activity of the three ligands using an in vitro system with human dendritic cells as the antigen-presenting cells and human NKT cells as the responding cells. Although 3 was a less potent agonist for NKT cells than 1 and 2, it induced cytokine production with the highest IFN-gamma:IL-4 and IFN-gamma:IL-13 ratios. Therefore, our data suggest that the new mimetic of alphaGalCer might preferentially promote Th1-immune responses and serve as a potent adjuvant in the immunotherapy of cancer and infectious diseases.
authors.affiliation: Department of Chemistry and Biochemistry, Queens College of The City University of New York, Flushing, NY 11367, USA.
authors.forename: Xuequan
authors.initials: X
authors.lastname: Lu
authors.forename: Liping
authors.initials: L
authors.lastname: Song
authors.forename: Leonid S
authors.initials: LS
authors.lastname: Metelitsa
authors.forename: Robert
authors.initials: R
authors.lastname: Bittman
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects; D005699:Galactosylceramides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006031:Glycosylation; D006801:Humans; D015394:Molecular Structure; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects*; D018417:Th1 Cells / Q000187:drug effects*
chemical_list: D016207:Cytokines; D005699:Galactosylceramides; C493154:alpha-galactosylceramide