Modification of the ceramide moiety of isoglobotrihexosylceramide on its agonist activity in stimulation of invariant natural killer T cells.
Isoglobotrihexosylceramide (iGb3) is an endogenous antigen of mammalian cells and can stimulate invariant natural killer T (iNKT) cells to evoke autoimmune activities by the release of T helper 1 (Th1) and Th2 cytokines. Th1 cytokines are correlated with the antitumor and antiviral response, while Th2 cytokines are correlated with the amelioration of autoimmune diseases. iGb3 is a very weak agonist compared to the exogenous alpha-galactosylceramide; however, modification of the ceramide moiety has been advocated as one of the approaches to improve its stimulatory activity and to change the bias of release of Th1 and Th2 cytokines. Two analogues of iGb3, 2H-iGb3 and HO-iGb3 with different ceramide moieties, were synthesized. Bioassay results showed that HO-iGb3 was much more effective in stimulating iNKT cells than iGb3 at low concentration. The assay also showed that the CD1d/2H-iGb3 complexes are remarkably efficient in stimulating iNKT cells.
Xia
Chengfeng
C
Departments of Biochemistry and Chemistry, The Ohio State University, 876 Biological Sciences Building, 484 West 12th Avenue, Columbus, Ohio 43210, and Experimental Immunology, Department of Research, University Hospital Basel, CH-4031 Basel, Switzerland.
Schümann
Jens
J
Emmanuel
Rossy
R
Zhang
Yalong
Y
Chen
Wenlan
W
Zhang
Wenpeng
W
De Libero
Gennaro
G
Wang
Peng George
PG
D018949:Antigens, CD1 / Q000378:metabolism; D055610:Antigens, CD1d; D002240:Carbohydrate Sequence; D002460:Cell Line; D005915:Globosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014281:Trihexosylceramides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D018949:Antigens, CD1; D055610:Antigens, CD1d; C526877:CD1D protein, human; D005915:Globosides; D011948:Receptors, Antigen, T-Cell; D014281:Trihexosylceramides; C514781:isoglobotrihexosylceramide; D015847:Interleukin-4; D007371:Interferon-gamma