Activation of invariant natural killer T cells by synthetic glycolipid ligands suppresses autoantibody-induced arthritis.

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.

CONCLUSION

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.