Preferential Th2 polarization by OCH is supported by incompetent NKT cell induction of CD40L and following production of inflammatory cytokines by bystander cells in vivo

Abstract

The altered glycolipid ligand OCH is a selective inducer of T(h)2 cytokines from NKT cells and a potent therapeutic reagent for T(h)1-mediated autoimmune diseases. Although we have previously shown the intrinsic molecular mechanism of preferential IL-4 production by OCH-stimulated NKT cells, little is known about the extrinsic regulatory network for IFN-gamma production. Here we demonstrate that OCH induces lower production of IFN-gamma, not only by NKT cells but also by NK cells compared with alpha-galactosylceramide. OCH induced lower IL-12 production due to ineffective primary IFN-gamma and CD40 ligand expression by NKT cells, and resulted in lower secondary IFN-gamma induction. Co-injection of a sub-optimal dose of IFN-gamma and stimulatory anti-CD40 mAb compensates for the lower induction of IL-12 by OCH administration. IL-12 converts OCH-induced cytokine expression from IL-4 predominance to IFN-gamma predominance. Furthermore, CpG oligodeoxynucleotide augmented IL-12 production when co-administrated with OCH, resulting in increased IFN-gamma production. Taken together, the lower IL-12 production and subsequent lack of secondary IFN-gamma burst support the effective T(h)2 polarization of T cells by OCH. In addition, highlighted in this study is the characteristic property of OCH that can induce the differential production of IFN-gamma or IL-4 according to the availability of IL-12.

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

“…We have previously shown that OCH, another analog of ␣-GalCer with a truncated sphingosine chain, preferentially induces Th2 cytokines (21)(22)(23). SGL-S23 administered in vivo induces more IFN␥ and less IL-4 compared with OCH and possesses a stronger ability to suppress inflammatory arthritis compared with ␣-GalCer or OCH (Kaieda S, et al: unpublished observations), indicating a unique property of this ligand.…”

“…IFN␥ was not induced in vivo by either S25 or S27. (23). Therefore, it seemed reasonable that lower initial IFN␥ production by iNKT cells would result in lower induction of IFN␥ at later time points.…”

“…Glycolipid ␣-GalCer and its analogs such as OCH, a sphingosine truncated form, have been shown to suppress autoimmune disease in animal models by inducing a Th2 response to autoantigen (13)(14)(15)(16)(17)(21)(22)(23)(24)(25). In autoantibodymediated arthritis such as the K/BxN serum transfer model, in which innate immune cells rather than lymphocytes are critical in the pathogenesis (6), iNKT cells have been shown to exaggerate the disease, probably by a mechanism other than modulation of the Th1/Th2 balance (26,27).…”

Cross-Regulation between Type I and Type II NKT Cells in Regulating Tumor Immunity: A New Immunoregulatory Axis

“…␣-GalCer (KRN7000), a strong agonist of type I NKT cells, has been reported to induce high IFN-␥ and IL-4 (37) with a preferential release of Th1 cytokines. OCH, a weaker agonist of type I NKT cells, has been reported to induce a higher ratio of IL-4/ IFN-␥ than ␣GalCer, leading to a suppression of a Th1-mediated autoimmune disease, experimental autoimmune encephalomyelitis (34,36,38). Because we have reported that a Th2 cytokine, IL-13, plays a critical role in the down-regulation of tumor immunosurveillance by NKT cells (10,13), to determine whether the final effect of type I NKT cell stimulation was due to preferential Th1 or Th2 cytokine induction, we stimulated type I NKT cells with either ␣GalCer or OCH.…”

Improved Outcomes in NOD Mice Treated with a Novel Th2 Cytokine-Biasing NKT Cell Activator

“…One of the most intensively studied examples of this is an ␣GalCer analog designated OCH, in which the fatty acid chain has been shortened to C24:0 and the sphingoid base truncated to C9. This analog is a relatively selective stimulator of IL-4 secretion and has pronounced anti-inflammatory effects in NOD mice and other mouse models of autoimmune disease (6,(11)(12)(13)(14)(15). Our earlier studies identified a novel derivative of KRN7000 containing an 11,14-cisdiunsaturated C20 fatty acid (␣GalCer C20:2) as a potent iNKT cell activator that powerfully stimulates production of IL-4 in association with reduced production of IFN-␥.…”