title: Activation of invariant natural killer T cells by synthetic glycolipid ligands suppresses autoantibody-induced arthritis.
abstract: OBJECTIVE
  Stimulation of invariant natural killer T (iNKT) cells with SGL-S23, a novel synthetic glycolipid analog of alpha-galactosylceramide with an elongated sphingosine chain, has been shown to strongly suppress K/BxN serum transfer arthritis. This study was designed to evaluate the protective effects of SGL-S23 in an effector phase of arthritis.
  
  
  METHODS
  To induce arthritis, C57BL/6 mice were injected with 150 mul of serum from K/BxN mice (KRN TCR-transgenic mice crossed with nonobese diabetic mice). Subsequently, synthetic glycolipid ligands were administered intraperitoneally twice, either 3 times starting on day 0 (the day of K/BxN serum injection) or twice starting on day 3. Neutralizing antibody against interferon-gamma (IFNgamma) interleukin-4 (IL-4), IL-10, or transforming growth factor beta was administered 4 hours before injection of SGL-S23. Recombinant IFNgamma was administered subcutaneously every day. The severity of arthritis was monitored using a macroscopic scoring system. Cytokine production and plasma histamine levels were measured by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  SGL-S23 strongly suppressed K/BxN serum transfer arthritis by inhibiting inflammatory cell infiltration and subsequent destruction of cartilage and bone. The inhibitory effect mediated by SGL-S23 was abolished by neutralization of IFNgamma. Systemic administration of IFNgamma prevented the development of inflammatory arthritis. Histamine release was suppressed by administration of SGL-S23 or IFNgamma. Degranulated mast cells in the synovium were significantly reduced in SGL-S23-treated mice, suggesting that suppression of mast cell activation contributed to the inhibition of arthritis.
  
  
  CONCLUSIONS
  These findings suggest that activation of iNKT cells with glycolipid ligands holds promise with regard to the treatment of autoimmune diseases such as rheumatoid arthritis. SGL-S23 has clinical benefit over alpha-galactosylceramide since it induces a weaker cytokine production response in iNKT cells, therefore reducing potential side effects caused by excessive cytokine release.
authors.affiliation: National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Shinjiro
authors.initials: S
authors.lastname: Kaieda
authors.forename: Chiharu
authors.initials: C
authors.lastname: Tomi
authors.forename: Shinji
authors.initials: S
authors.lastname: Oki
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamura
authors.forename: Sachiko
authors.initials: S
authors.lastname: Miyake
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D001323:Autoantibodies / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D005699:Galactosylceramides / Q000494:pharmacology*; D006017:Glycolipids / Q000494:pharmacology*; D006632:Histamine / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology*; D008024:Ligands; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D000276:Adjuvants, Immunologic; D001323:Autoantibodies; D016207:Cytokines; D005699:Galactosylceramides; D006017:Glycolipids; D008024:Ligands; C493154:alpha-galactosylceramide; C521183:suppressor glycolipid S23; D006632:Histamine; D007371:Interferon-gamma