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

• Published in: Clinical and experimental immunology 2011-05, Vol.164 (2), p.236-247
• Main Authors: Yoshiga, Y., Goto, D., Segawa, S., Horikoshi, M., Hayashi, T., Matsumoto, I., Ito, S., Taniguchi, M., Sumida, T.
• Format: Article
• Language: English
• Subjects: Analytical, structural and metabolic biochemistry; Animal Models; Animals; Antibody Formation - drug effects; Arthritis, Experimental - chemically induced; Arthritis, Experimental - drug therapy; Arthritis, Experimental - immunology; Autoimmune Diseases - chemically induced; Autoimmune Diseases - drug therapy; Autoimmune Diseases - immunology; Biological and medical sciences; Cattle; Collagen Type II - toxicity; collagen‐induced arthritis; Diseases of the osteoarticular system; Drug Evaluation, Preclinical; Fundamental and applied biological sciences. Psychology; Galactosylceramides - pharmacology; Galactosylceramides - therapeutic use; glycolipid ligand; Immunologic Factors - therapeutic use; Inflammatory joint diseases; Interferon-gamma - biosynthesis; Interferon-gamma - genetics; Interferon-gamma - secretion; Interleukin-23 - biosynthesis; Interleukin-23 - genetics; Interleukin-6 - biosynthesis; Interleukin-6 - genetics; Ligands; Lymph Nodes - immunology; Lymph Nodes - pathology; Lymphocyte Activation - drug effects; Male; Medical sciences; Mice; Mice, Inbred DBA; natural killer T cells; Natural Killer T-Cells - drug effects; Natural Killer T-Cells - immunology; Natural Killer T-Cells - secretion; Specific Pathogen-Free Organisms; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; Th1; Th1 Cells - drug effects; Th1 Cells - immunology; Th1 Cells - secretion; Th17; Th17 Cells - drug effects
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/j.1365-2249.2011.04369.x

Summary Alpha‐carba‐GalCer (RCAI‐56), a novel synthetic analogue of α‐galactosylceramide (α‐GalCer), stimulates invariant natural killer T (NK T) cells to produce interferon (IFN)‐γ. IFN‐γ 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 α‐carba‐GalCer on collagen‐induced arthritis (CIA) in mice. First, we confirmed that α‐carba‐GalCer selectively induced IFN‐γ in CIA‐susceptible DBA/1 mice in vivo. Then, DBA/1 mice were immunized with bovine type II collagen (CII) and α‐carba‐GalCer. The incidence and clinical score of CIA were significantly lower in α‐carba‐GalCer‐treated mice. Anti‐IFN‐γ antibodies abolished the beneficial effects of α‐carba‐GalCer, suggesting that α‐carba‐GalCer ameliorated CIA in an IFN‐γ‐dependent manner. Treatment with α‐carba‐GalCer reduced anti‐CII antibody production [immunoglobulin (Ig)G and IgG2a] and CII‐reactive 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‐γ‐producing T cells to IL‐17‐producing T cells (Th1/Th17 ratio). Moreover, the gene expression levels of IL‐6 and IL‐23p19, Th17‐related cytokines, were reduced significantly in mice treated with α‐carba‐GalCer. In addition, we observed higher IFN‐γ production by NK T cells in α‐carba‐GalCer‐treated mice in the initial phase of CIA. These findings indicate that α‐carba‐GalCer polarizes the T cell response toward Th1 and suppresses Th17 differentiation or activation, suggesting that α‐carba‐GalCer, a novel NK T cell ligand, can potentially provide protection against Th17‐mediated autoimmune arthritis by enhancing the Th1 response.