Activation of natural killer T cells by α-carba-GalCer (RCAI-56), a novel synthetic glycolipid ligand, suppresses murine collagen-induced arthritis

Abstract

SummaryAlpha-carba-GalCer (RCAI-56), a novel synthetic analogue of agalactosylceramide (a-GalCer), stimulates invariant natural killer T (NK T) cells to produce interferon (IFN)-g. IFN-g exhibits immunoregulatory properties in autoimmune diseases by suppressing T helper (Th)-17 cell differentiation and inducing regulatory T cells and apoptosis of autoreactive T cells. Here, we investigated the protective effects of a-carba-GalCer on collageninduced arthritis (CIA) in mice. First, we confirmed that a-carba-GalCer selectively induced IFN-g in CIA-susceptible DBA/1 mice in vivo. Then, DBA/1 mice were immunized with bovine type II collagen (CII) and a-carbaGalCer. The incidence and clinical score of CIA were significantly lower in a-carba-GalCer-treated mice. Anti-IFN-g antibodies abolished the beneficial effects of a-carba-GalCer, suggesting that a-carba-GalCer ameliorated CIA in an IFN-g-dependent manner. Treatment with a-carba-GalCer reduced anti- Th17 ratio). Moreover, the gene expression levels of IL-6 and IL-23p19, Th17-related cytokines, were reduced significantly in mice treated with a-carba-GalCer. In addition, we observed higher IFN-g production by NK T cells in a-carba-GalCer-treated mice in the initial phase of CIA. These findings indicate that a-carba-GalCer polarizes the T cell response toward Th1 and suppresses Th17 differentiation or activation, suggesting that a-carbaGalCer, a novel NK T cell ligand, can potentially provide protection against Th17-mediated autoimmune arthritis by enhancing the Th1 response. CII antibody production [immunoglobulin (Ig)G and IgG2a] and CIIreactive interleukin (IL)-17 production by draining lymph node (DLN) cells, did not induce apoptosis or regulatory T cells, and significantly increased the ratio of the percentage of IFN-g-producing T cells to IL-17-producing T cells (Th1/

Activation of Invariant NKT Cells with Glycolipid Ligand α-Galactosylceramide Ameliorates Glucose-6-Phosphate Isomerase Peptide-Induced Arthritis

“…Kaieda et al showed that SGL-S23, an analog of α-GalCer, had suppressive effect on K/BxN serum transfer arthritis through IFN-γ [26]. We previously showed that α-carba-GalCer, an analog of α-GalCer, suppressed the severity of CIA through the induction of Th1-biased differentiation of CD4+ T cells [20]. In contrast to these studies, α-GalCer suppressed both Th1 and Th17 CD4+ T cells in GPI peptide-induced arthritis.…”

“…The draining lymph nodes (dLN) and splenocytes were isolated as described previously [20]. Single-cell suspensions were prepared in Roswell Park Memorial Institute (RPMI) 1640 medium (Sigma-Aldrich) containing 10% fetal bovine serum (FBS), penicillin–streptomycin (100 U/ml), 10 mM HEPES buffer solution (Gibco BRL, Grand Island, NY), 0.1 mM MEM nonessential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), and 5.5 mM 2-mercaptoethanol (2-ME).…”

Transitioning from Idiopathic to Explainable Autoimmune Hepatitis

“…As the inhibitory and stimulatory actions of the NKT cells are better understood, interventions can be developed that modulate their effects in a favorable, disease-specific fashion [289][290][291].…”

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

“…As early as day 3, DLN cells expressed reduced IL-6 and IL23p19 with unchanged TGF-ϐ while CD1d-tetramer + iNKT cells produced higher IFN-in spleen, liver and DLN. On day 10, DLN T cells stimulated with PMA and ionomycin showed polarisation towards Th1 and suppression of Th17 cell differentiation, in keeping with protective Th1 deviation during the initiation phase of CIA (Yoshiga et al, 2011).…”