A multifactorial mechanism in the superior antimalarial activity of alpha-C-GalCer.
We have previously shown that the C-glycoside analog of alpha-galactosylceramide (alpha-GalCer), alpha-C-GalCer, displays a superior inhibitory activity against the liver stages of the rodent malaria parasite Plasmodium yoelii than its parental glycolipid, alpha-GalCer. In this study, we demonstrate that NK cells, as well as IL-12, are a key contributor for the superior activity displayed by alpha-C-GalCer. Surprisingly, the diminished production of Th2 cytokines, including IL-4, by alpha-C-GalCer has no affect on its superior therapeutic activity relative to alpha-GalCer. Finally, we show that the in vivo administration of alpha-C-GalCer induces prolonged maturation of dendritic cells (DCs), as well as an enhanced proliferative response of mouse invariant Valpha14 (Valpha14i) NKT cells, both of which may also contribute to some degree to the superior activity of alpha-C-GalCer in vivo.
Schmieg
John
J
Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Yang
Guangli
G
Franck
Richard W
RW
Tsuji
Moriya
M
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D015536:Down-Regulation / Q000187:drug effects; D005699:Galactosylceramides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006027:Glycosides; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008288:Malaria / Q000188:drug therapy / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D009005:Monosaccharides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism
D000962:Antimalarials; C550181:C-galactosylceramide; C438934:C-glycoside; D005699:Galactosylceramides; D006027:Glycosides; D009005:Monosaccharides; D011948:Receptors, Antigen, T-Cell; C493154:alpha-galactosylceramide; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4