Suppression of collagen‐induced arthritis by natural killer T cell activation with OCH, a sphingosine‐truncated analog of α‐galactosylceramide

Abstract

Objective. OCH, a synthetic analog of ␣-galactosylceramide with a truncated sphingosine chain, stimulates natural killer T (NKT) cells to produce predominantly Th2 cytokines. Thus, OCH may be a potential agent for the treatment of Th1-mediated autoimmune diseases. This study was designed to evaluate the protective effects of OCH on collagen-induced arthritis (CIA) in mice.Methods. Mice were immunized with type II collagen (CII) and injected intraperitoneally twice per week with OCH, before or after the onset of CIA. They were monitored to assess the effect of OCH treatment on the severity of disease. Anti-CII antibodies and cytokine production were measured by enzyme-linked immunosorbent assay. Expression of cytokine genes was determined by quantitative reverse transcriptasepolymerase chain reaction.Results. OCH inhibited CIA in wild-type C57BL/6 (B6) mice but not in NKT-deficient mice. OCH suppressed CIA in SJL mice, which are prone to autoimmune diseases and have a deficiency in the number and function of NKT cells which is similar to that in patients with autoimmune diseases, even after disease has already developed. Disease protection conferred by OCH correlated with its ability to selectively induce Th2 cytokine production mediated by NKT cells and to promote collagen-specific Th2 responses. Neutralization of interleukin-4 (IL-4) or IL-10 with monoclonal antibodies abolished disease protection by OCH, indicating a critical role for these cytokines. Conclusion. Taken together, our findings suggest that OCH holds possibilities as a therapeutic agent for autoimmune diseases such as rheumatoid arthritis.Rheumatoid arthritis (RA) is a common autoimmune disease characterized by persistent inflammation of joints resulting in progressive destruction of cartilage and bone. Although its precise etiology is not clearly understood, cumulative evidence suggests that Th1 cells secreting interferon-␥ (IFN␥) and tumor necrosis factor ␣ (TNF␣) exacerbate disease, whereas Th2 cells producing interleukin-4 (IL-4) and IL-10 suppress arthritis (1). Studies with animal models have demonstrated that systemic or locally administered IL-4 and IL-10 can effectively protect against arthritis in mice (2-11).Natural killer T (NKT) cells are a unique subset of T cells that coexpress T cell receptor ␣/␤ (TCR␣/␤) and receptors from the NK lineage. NKT cells express an invariant TCR␣ chain (encoded by a V ␣ 14-J ␣ 281 rearrangement in mice and a homologous V ␣ 24-J ␣ Q rearrangement in humans). Unlike conventional T cells that recognize peptides in association with major histocompatibility complex (MHC), NKT cells recognize glycolipid antigens bound to the nonpolymorphic class I MHC-like protein, CD1d. NKT cells have been implicated in a variety of immune responses such as infection and tumor immunity. One striking feature of NKT cells is their capacity to secrete a large amount of cytokines,

NKT Cells in Tumor Immunity: Opposing Subsets Define a New Immunoregulatory Axis

“…Type I NKT cells have also been found to protect against EAE by other mechanisms in TCR V␣14J␣18-transgenic NOD mice (79) or in mice treated with ␣GalCer and challenged with an EAE-inducing myelin oligodendrocyte glycoprotein (MOG) peptide (80), in both cases apparently not involving Th2 cytokines. A similar treatment with OCH to induce Th2 cytokine production by type I NKT cells was also protective in a mouse model of collagen-induced arthritis (81).…”

Critical Role for the Chemokine Receptor CXCR6 in Homeostasis and Activation of CD1d-Restricted NKT Cells

“…Treatment with ␣-GalCer or ␣-GalCer-loaded dendritic cells (DC) induces a potent antitumor response by stimulating IFN-␥ production (24 -26), while ␣-GalCer has also been shown to ameliorate autoimmunity through the induction of Th2 responses (27)(28)(29). In contrast to the ability of ␣-GalCer to generate both Th1 and Th2 cytokines, OCH, a truncated derivative of ␣-GalCer, induces a preferential Th2 response that can suppress experimental autoimmune encephalitis and collagen-induced arthritis (30,31), whereas the C-glycoside derivative ␣-C-GalCer induces a selective Th1 response and is very effective at preventing tumor metastasis (32). Although the nature of the glycolipid Ag influences the NKT cell response, costimulatory molecules are also important.…”

Natural killer T cells ameliorate antibody-induced arthritis in macrophage migration inhibitory factor transgenic mice

“…·-GalCer was used to treat mice with anti-IIC mAb/LPS-induced arthritis. Starting at day 3 after anti-IIC mAb/LPS treatment, mice were injected intraperitoneally twice per week with ·-GalCer at a dose of 0.5 μg/g BW (14). The control mice were injected with vehicle alone (0.05% polysorbate at final concentration) in phosphatebuffered saline (PBS).…”

“…It has been reported that NKT cells activated by the ·-GalCer analogue OCH protect against arthritis by promoting Th2-biased immune deviation (14). To examine NKT cellmediated immunomodulation in our experimental model, we first analyzed the size of the NKT population in spleens of MIF Tg and WT mice, before and after administration of the anti-CII mAb/LPS.…”

“…It has been reported that administration of neutralizing anti-MIF antibody (Ab) protects mice from CIA (12) and anti-IIC mAb/LPS-induced arthritis (13). In the CIA model, administration of OCH, a sphingosine-truncated analogue of ·-galactosylceramide (·-GalCer) that functions as a prototypical ligand for natural killer T (NKT) cells, to C57BL/6 (B6) mice inhibited arthritis (14). This finding suggests a protective role of glycolipidactivated NKT cells in arthritis.…”