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Brief Treatment with iNKT Cell Ligand α-Galactosylceramide Confers a Long-term Protection Against Lupus

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Abstract

CD1d presents glycolipid antigens such as α-galactosylceramide (αGalCer) to invariant natural killer T cells (iNKT). We have reported that activated iNKTs inhibit IL-10-producing autoreactive B cells, while promoting or leaving intact the normal B cell responses, making iNKT modulation an attractive therapeutic modality. Here, we report that a brief treatment of young lupus-prone (NZB/NZW)F1 (BWF1) mice with two injections of αGalCer conferred a long-term protection against lupus. Long-term repeated administrations of αGalCer, however, afforded no clinical benefit. These disparate clinical effects correlated with iNKT responsiveness. While a brief treatment with αGalCer enhanced iNKT responses upon in vitro recall, the long-term αGalCer treatment resulted in reduced iNKT responses in BWF1 mice. The improvement in disease with αGalCer treatment was associated with the reduced IL-10 production. Furthermore, iNKTs directly inhibited IL-10-secreting cells in vivo in reconstituted SCID mice and inhibited IL-10-secreting B cells in vitro in co-cultures. Thus, a brief treatment with a CD1d-binding glycolipid enhances iNKT responses, reduces IL-10 production, and delays the onset of lupus, whereas long-term repeated treatments induce marked iNKT hyporesponsiveness and do not affect disease outcome in BWF1 mice. Identifying glycolipid regimens that can modulate iNKT responsiveness will have important implications for developing iNKT-based therapies for autoimmune diseases.

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Acknowledgments

This work was supported in part by grants from National Institutes of Health (AR47322, AR50797, AR56465, and AI80778) and the American Heart Association (Beginning-Grant-in-Aid to PJK).

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Authors and Affiliations

  1. Autoimmunity and Tolerance Laboratory, Division of Rheumatology, Department of Medicine, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, 90095, USA

    Jun-Qi Yang, Peter J. Kim & Ram Raj Singh

  2. University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA

    Jun-Qi Yang & Ram Raj Singh

  3. Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu, China

    Jun-Qi Yang

  4. Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA, 90095, USA

    Ram Raj Singh

  5. Jonsson Comprehensive Cancer Center, UCLA, 1000 Veteran Avenue, Room 32-59 Rehab Center, Los Angeles, CA, 90095-1670, USA

    Ram Raj Singh

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  1. Jun-Qi Yang
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Correspondence to Ram Raj Singh.

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Yang, JQ., Kim, P.J. & Singh, R.R. Brief Treatment with iNKT Cell Ligand α-Galactosylceramide Confers a Long-term Protection Against Lupus. J Clin Immunol 32, 106–113 (2012). https://doi.org/10.1007/s10875-011-9590-y

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  • DOI: https://doi.org/10.1007/s10875-011-9590-y

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