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 ␣-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 l 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-␥ (IFN␥) interleukin-4 (IL-4), IL-10, or transforming growth factor ␤ was administered 4 hours before injection of SGL-S23. Recombinant IFN␥ 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 IFN␥. Systemic administration of IFN␥ prevented the development of inflammatory arthritis. Histamine release was suppressed by administration of SGL-S23 or IFN␥. 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 ␣-galactosylceramide since it induces a weaker cytokine production response in iNKT cells, therefore reducing potential side effects caused by excessive cytokine release.

Invariant Natural Killer T Cells in Rheumatoid Arthritis and Other Inflammatory Arthritides

“…Similarly, in vivo injection of SGL-S23 resulted in weaker IFN-serum responses. In keeping with the known essential role played by mast cells in the development of arthritis in the K/BxN serum transfer model, Kaieda et al (2007) showed an elevation in serum histamine level five minutes after serum injection, abolished by pre-treatment with low-dose IFN-. SGL-S23 also suppressed histamine release, and more effectively so than α-GalCer or high dose IFN-.…”

“…Screening a panel of analogs of α-GalCer for the ability to suppress the development of arthritis in a B6 model of K/BxN serum transfer-induced arthritis, Kaieda et al (2007) found SGL-S23, an analog with a 5-carbon longer sphingosine base that could inhibit clinical and histological disease severity to a greater degree than α-GalCer by i.p. administration on days 0, 3 and 7.…”

High doses of α-galactosylceramide potentiate experimental autoimmune encephalomyelitis by directly enhancing Th17 response

“…iNKT cells show a remarkable functional diversity, and elicit varying and opposing immune functions. On the one hand, they actively induce T-cell tolerance and are crucial for the prevention of autoimmune diseases in pre-clinical models of MS [16,17], type 1 diabetes [18,19], systemic lupus erythematosus [20], myasthenia gravis [21] and rheumatoid arthritis [22,23]. On the other hand, iNKT cells participate in the innate immune response to promote antimicrobial [24][25][26] and antitumor [27][28][29][30] immunity.…”

In Vivo Protection Provided by a Synthetic New Alpha-Galactosyl Ceramide Analog against Bacterial and Viral Infections in Murine Models

“…However, the effectiveness of ␣-GalCer is limited by the opposing effects of the Th1 and Th2 cytokines induced by this glycolipid. In order to develop selective Th1 or Th2 activators, many ␣-GalCer analogs were synthesized (1,3,5,8,12,14,21,34,36), and their immune-modulating activities were shown to be related to the affinity of binding to CD1d (8). Recent studies using a CD1d array established that the secretion of IFN-␥ and IL-4 by NKT cells is determined by the binding of ␣-GalCer analogs to CD1d (21), and a higher affinity for CD1d would shift the cytokine release profile toward a stronger Th1 response (3,21).…”