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A Single Early Activation of Invariant NK T Cells Confers Long-Term Protection against Collagen-Induced Arthritis in a Ligand-Specific Manner¹

Ken Coppieters^2,*,, Katrien Van Beneden^2,*, Peggy Jacques^*, Pieter Dewint^*, Ann Vervloet^*, Bert Vander Cruyssen^*, Serge Van Calenbergh, Guangwu Chen^¶, Richard W. Franck^¶, Gust Verbruggen^*, Dieter Deforce^||, Patrick Matthys, Moriya Tsuji^#, Pieter Rottiers and Dirk Elewaut^3,*

^* Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent University, Ghent, Belgium; Department for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology and Ghent University, Ghent, Belgium; Laboratory of Medicinal Chemistry, Ghent University, Ghent, Belgium; Laboratory of Immunobiology, Rega Institute, Katholieke Universiteit Leuven, Leuven, Belgium; ^¶ Department of Chemistry and Biochemistry, Hunter College, City University of New York, New York, NY 10021; ^|| Laboratory for Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium; and ^# Aaron Diamond AIDS Research Center, Rockefeller University, New York, NY 10016

The glycosphingolipid -galactosylceramide (-GalCer) has been shown to be a potent activator of invariant NKT (iNKT) cells, rapidly inducing large amounts of both Th1 and Th2 cytokines upon injection in mice. The C-glycoside analog of -GalCer (-C-GalCer), by contrast, results in an enhanced Th1-type response upon activation of iNKT cells. We administered a single dose of these Ags to DBA/1 mice during the early induction phase of collagen-induced arthritis and demonstrated therapeutic efficacy of -GalCer when administered early rather than late during the disease. Surprisingly, the Th1-polarizing analog -C-GalCer also conferred protection. Furthermore, a biphasic role of IFN- in the effect of iNKT cell stimulation was observed. Whereas in vivo neutralization of IFN- release induced by either -GalCer or -C-GalCer early during the course of disease resulted in partial improvement of clinical arthritis symptoms, blockade of IFN- release later on resulted in a more rapid onset of arthritis. Although no phenotypic changes in conventional T cells, macrophages, or APCs could be detected, important functional differences in T cell cytokine production in serum were observed upon polyclonal T cell activation, 2 wk after onset of arthritis. Whereas -GalCer-treated mice produced significantly higher amounts of IL-10 upon systemic anti-CD3 stimulation compared with PBS controls, T cells from -C-GalCer-treated mice, by contrast, produced substantially lower levels of cytokines, suggesting the involvement of different protective mechanisms. In conclusion, these findings suggest long-term, ligand-specific, time-dependent, and partially IFN--dependent immunomodulatory effects of iNKT cells in collagen-induced arthritis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Concerted Action Grant GOA2001/12051501 of Ghent University, and by grants of the Research Foundation-Flanders, the Research Council of Ghent University, and the Flanders Interuniversity Institute for Biotechnology.

² K.C. and K.V.B. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Dirk Elewaut, Ghent University Hospital, Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, 185 De Pintelaan, B-9000 Ghent. E-mail address: Dirk.Elewaut{at}UGent.be

⁴ Abbreviations used in this paper: iNKT, invariant NKT; -GalCer, -galactosylceramide; -C-GalCer, C-glycoside analog of -GalCer; CBA, cytometric bead array; CIA, collagen-induced arthritis; CII, collagen type II; m, murine.

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