Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Clin Immunol. Author manuscript; available in PMC 2012 Sep 2.
Published in final edited form as:
PMCID: PMC3432318

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


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.

Keywords: Rodent, T cells, autoimmunity, systemic lupus erythematosus


Invariant natural killer T cell (iNKT) is a subset of T cells that recognize lipid antigens, such as α-galactosylceramide (αGalCer), in the context of the non-classical MHC class I molecule CD1d [13]. We have recently reported that iNKTs inhibit the production of autoantibodies that are the hallmark of autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis [4]. Consistent with the protective role of iNKT cells in autoantibody-mediated diseases, genetically lupus-susceptible (NZB×NZW)F1 (BWF1) mice rendered deficient in CD1d experience worse lupus nephritis than their wild-type littermates [5]. Similar results were reported using another model where autoantibody production is triggered by increased load of circulating apoptotic cells [6]. The absence or reduction of iNKTs as well as the absence of CD1d expression on B cells led to increased autoreactive B cell activation and symptoms of lupus-like disease, which was rescued by transferring iNKTs to deficient mice [6]. Intriguingly, while iNKTs reduce the production of rheumatoid factor and anti-DNA autoantibodies, these cells simultaneously increase total IgG levels and augment the production of antibodies against exogenous antigens [4]. iNKTs accomplish such precise, seemingly paradoxical, regulation of B cell subsets via CD1d that is expressed at a higher level on autoreactive B cells than on non-autoreactive B cells [4]. Such ability of iNKTs to differentially regulate normal versus autoreactive B cells makes them an ideal therapeutic target.

Compared to healthy subjects, patients with SLE and their relatives have reduced NKT cell numbers [79], suggesting that NKT cell impairment is a heritable trait. The reduced iNKT numbers in the relatives of patients with SLE correlate with the presence of autoimmunity [7]. Furthermore, whereas invariant Vα24JαQ (Vα24Jα18) T cell receptor (TCR) dominates double negative Vα24+ T cells at a high frequency in healthy subjects, this invariant TCR was reduced to undetectable levels in Vα24+ T cells from patients with active SLE [10]. Vα24Jα18+ T cells were restored to normal levels when patients were treated with corticosteroids [10]. Finally, whereas Vα24+Vβ11+ double negative T cells from healthy subjects proliferated in the presence of αGalCer, five of the ten SLE patients tested exhibited no such response to αGalCer [8]. These data support a role of iNKT impairments in patients with SLE. In vivo treatments that can correct these NKT cell impairments might be of therapeutic value.

Here, we investigated the clinical effects, iNKT responses, and cytokine production in BWF1 mice treated with αGalCer. Results show that a brief treatment with αGalCer augments iNKT responses and confers long-term protection against lupus. A long-term repeated treatment with αGalCer, however, elicits selective iNKT hyporesponsiveness and affords no clinical benefit.

Materials and Methods


BALB/c SCID, NZB, and NZW mice were purchased from the Jackson Laboratory (Bar Harbor, ME, USA). NZB and NZW mice were bred locally to generate BWF1 mice that develop T cell-dependent autoantibody-mediated lupus nephritis [11]. Animals used were bred and housed in animal colonies at the University of Cincinnati and UCLA. Vα14Tg BALB/c mice that are transgenic for iNKT TCR [12] and Jα18−/− BALB/c mice that have no iNKTs [13] were provided by Dr. A. Bendelac and Dr. M. Taniguchi, respectively. Female mice were used in all experiments. Experiments were performed according to the approved institutional guidelines.

αGalCer Treatment

Synthetic αGalCer (KRN 7000) was kindly provided by Kyowa Hakko Kirin Co. Ltd. (Tokyo, Japan). Animals were treated twice a week i.p. with 4–6 µg αGalCer or the same volume of control vehicle (0.025% polysorbate-20 in PBS).

Assessment of Lupus Disease

Proteinuria was measured on a 0–4+ scale using a colorimetric assay strip for albumin (Albustix, Bayer Co., Elkhart, IN), where 0=absent, 1+≤30 (mild), 2+=100 (moderate), 3+=300, and 4+≥2,000 mg/dl (severe). Severe proteinuria was defined as ≥300 mg/dl on two consecutive examinations, as described previously [14]. IgG anti-DNA Abs were measured by ELISA, as described [5, 14]. Anti-DNA Ab titers are expressed as units per milliliter (U/ml) using a reference-positive standard of pooled serum from 1-year-old BWF1 mice. Experiments shown in Fig. 1 versus Fig. 2 used different sets of standard serum. Hence, the results of anti-double-stranded DNA (dsDNA) antibodies are not comparable between Figs. 1 and and22.

Fig. 1
A brief treatment with αGalCer confers long-term protection from lupus in BWF1 mice. Seven-week-old BWF1 mice were treated with αGalCer (4 µg i.p.) or vehicle twice at a 3-day interval. a Results are shown as the percentage of ...
Fig. 2
Long-term repeated administration of αGalCer does not protect from lupus in BWF1 mice. Five-week-old mice at a preclinical stage, i.e., without circulating anti-dsDNA Abs or proteinuria (n=22 mice per group; a, d); 18-week-old mice with early ...

Cytokine Assay

Spleen cells (106 cells per ml) were cultured in RPMI 1640 medium supplemented with 10% FCS, 2×10−5 M 2-ME, 20 mM HEPES, 1 mM sodium pyruvate, and 100 µg/ml gentamicin and various stimulants as described in the figure legends. Supernatants collected were assayed for cytokine levels by ELISA, as described [5].

Flow Cytometry Analysis

Freshly prepared or cultured spleen cells were incubated with anti-CD16/32 (2.4 G2, PharMingen) to block FcγRII/III, followed by staining with various conjugated mAbs (all PharMingen), as indicated in the figure legends. iNKTs were identified by CD1d/αGalCer tetramer staining, as described [15]. Stained cells were analyzed using a Becton Dickinson FACSCalibur flow cytometer (Mountain View, CA, USA) and CellQuest software. Absolute cell numbers of each cell subset were calculated by the percentage of staining cells times total cell numbers.

Cytokine Secretion Assay

We detected IL-10-secreting cells using the MACS Cytokine Secretion Assay Kit (Miltenyi Biotec, Auburn, CA, USA), as described [4, 15, 16]. Briefly, spleen cells prepared from the reconstituted BALB/c SCID mice or cells from the mixed cultures of Vα14Tg T cells plus Jα18−/− B cells were incubated at 37°C for 45 min with the cytokine Catch Reagent that attaches to all leukocytes via CD45 antigen and binds to the specific cytokine. After washing, cells were stained with PE-conjugated IL-10 detection mAbs, counterstained with anti-CD11b mAb, and analyzed using FACSCalibur.

SCID Reconstitution Experiment

B cells were purified from the spleen of Jα18−/− mice using anti-CD45R (B220) microbeads on an autoMACS magnetic cell separator (Miltenyi Biotec, Auburn, CA, USA). Jα18−/− B cells were used to avoid any contaminating iNKTs. Ten million of these B cells (>97% pure) were injected i.v. into BALB/c SCID mice. The B cell-reconstituted SCID mice were then transferred i.v. with six million iNKTs (TCRβ+CD1d-αGalCer dimer+), which were enriched from the spleen of Vα14Tg mice, as described [4]. The purity of iNKTs was >92%. Control animals received the same numbers of B220+ cell-depleted spleen cells from Jα18−/− mice. Animals received an i.p. injection each of 5 µg LPS and 4–6 µg αGalCer separately prior to reconstitution with cells. To verify the reconstitution, spleen cells harvested from these mice were analyzed for TCRβ+CD1d-αGalCer dimer+ cells 4 days after the transfer, as described previously [4]. As expected, the recipients of Vα14Tg T cells had iNKTs, whereas recipients of Jα18−/− T cells had no iNKTs. Spleen cells from the reconstituted mice were analyzed for IL-10-secreting cells using the above described cytokine secretion assay.


The statistical significance was analyzed using Student’s t test or Mann–Whitney U test. Differences were considered significant when p value was<0.05. Proportions of mice with proteinuria were compared using a log-rank test.


A Brief Treatment with αGalCer Confers a Long-term Protection Against Lupus Nephritis

To determine the in vivo effects of iNKTs on spontaneously developing autoantibody-mediated disease, we treated BWF1 mice with αGalCer or vehicle and monitored them for clinical evidence of nephritis and serum IgG anti-dsDNA Ab. Remarkably, treatment of young BWF1 mice with only two αGalCer injections led to a prolonged reduction in renal disease and IgG anti-DNA Abs (Fig. 1). The 50% prevalence of severe proteinuria was delayed by 17 weeks in αGalCer-treated animals compared to vehicle-injected control animals. Thus, in vivo iNKT activation for a brief period can confer a long-term protective effect on lupus disease.

Long-term, Repeated Administration of αGalCer Has No Effect on Lupus Nephritis

We then determined the effect of long-term, repeated administrations of αGalCer on lupus disease. We found that long-term treatment in mice at a preclinical stage (Fig. 2a), in mice with early clinical disease (Fig. 2b), or in mice having full-blown disease (Fig. 2c) had no effect on disease progression, as indicated by proteinuria and serum IgG anti-dsDNA Ab. Thus, in contrast to the above protective effects of short-term αGalCer treatment, the long-term continuous treatment of BWF1 mice had no significant effect on lupus nephritis.

Brief αGalCer Exposure Boosts iNKT Responses, Whereas Long-term Repeated αGalCer Treatments Reduce iNKT Responsiveness in BWF1 Mice

To assess the mechanisms underlying the disparate clinical effects of short-term versus long-term αGalCer regimens, we first analyzed iNKT responses after single or multiple repeated injections of αGalCer in BWF1 mice. Young BWF1 mice were injected once with vehicle or αGalCer, and their spleen cells cultured with increasing concentrations of αGalCer. As expected from previous studies in normal animals, addition of αGalCer to cultures of spleen cells from control, vehicle-injected BWF1 mice elicited increases in IFN-γ, IL-13, and IL-4 levels and in spleen cell proliferation. The levels of these cytokines and spleen cell proliferation were significantly higher, however, in mice that were primed in vivo with αGalCer (Fig. 3). Thus, brief in vivo priming with a glycolipid antigen boosts iNKT responses in lupus-prone mice.

Fig. 3
Effect of short-term administration of αGalCer on iNKT cell responses in BWF1 mice. a Cytokine responses. Seven-week-old BWF1 mice were injected i.v. once with 4 µg αGalCer or vehicle alone (five mice per group). Spleen cells from ...

Next, we analyzed iNKT cell responses to long-term repeated treatments with αGalCer inBWF1 mice. Surprisingly, we found that administration of αGalCer twice a week for >10 weeks resulted in an almost complete iNKT cell unresponsiveness as compared to vehicle-injected control BWF1 mice (Fig. 4). This unresponsiveness is glycolipid antigen-specific, since Con A and anti-CD3 elicited similar cytokine responses in αGalCer- and vehicle-injected mice (Fig. 4). Such iNKT cell unresponsiveness is not associated with attrition in iNKT cell numbers after long-term repeated exposures to a glycolipid antigen, as shown in Fig. 5.

Fig. 4
Effect of long-term administration of αGalCer on iNKT cell responses in BWF1 mice. Nine-week-old female BWF1 mice were treated with αGalCer (4 µg i.p. twice a week) or control vehicle for 3 months. Three months later, mice were ...
Fig. 5
Effect of αGalCer treatment on iNKT cell numbers in BWF1 mice. Seven- to 9-week-old BWF1 mice were treated with αGalCer (4 µg i.p. twice a week) or equal volume of vehicle for a short-term (1 week, as described in Fig. 1a) (a) ...

αGalCer Treatment of Young BWF1 Mice Reduces IL-10 Production

To begin to investigate the mechanisms underlying αGalCer-mediated improvement in disease in BWF1 mice shown in Fig. 1, we measured cytokines, IL-2, IL-4, IL-10, IL-13, TGFβ1, and IFN-γ in spleen cell culture supernatants of BWF1 mice ≥6 months after treatment with two injections of αGalCer. IL-10 production was consistently lower in spleen cell cultures of αGalCer-treated than in vehicle-injected BWF1 mice (Fig. 6a), whereas other cytokines were increased or unchanged compared to vehicle-injected control mice (data not shown).

Fig. 6
Effect of αGalCer treatment on IL-10 production. a Spleen cells were harvested from BWF1 mice ≥6 months after treatment with αGalCer or vehicle (as in Fig. 1) and cultured with LPS without or with αGalCer. Supernatants ...

Reduced IL-10 levels in αGalCer-treated BWF1 mice could be due to reduced numbers of IL-10-producing cells owing to improved disease or due to a direct of iNKT cells on IL-10-producing cells. To test the possibility that iNKTs directly reduce IL-10-producing cells, we conducted adoptive transfer studies in SCID mice that were implanted with B cells (from Jα18−/− mice to avoid any contaminating iNKT cells). As shown in Fig. 6b, B cell-reconstituted SCID mice that were transferred with isolated iNKTs had lower numbers of IL-10-producing cells than SCID mice that received no iNKTs (i.e., Jα18−/− T cells). Thus, iNKTs can directly reduce IL-10-producing cells in vivo.

To further investigate if iNKTs inhibit IL-10 production by B cells, as reported recently [4], we co-cultured Vα14Tg T cells and Jα18−/− B cells with LPS or CpG and enumerated IL-10-secreting B cells. Vα14Tg T cells were used in these experiments as a rich source of iNKT cells as well as to obviate the possibility that iNKT cells might have undergone anergy or activation-induced cell death during their isolation using dimers in Fig. 6b. Results show that the addition of αGalCer to LPS or CpG-containing cultures resulted in 1.7–1.8-fold reduction in the proportion and numbers of IL-10-secreting B cells (Fig. 6c). Taken together, these data suggest that αGalCer-activated iNKTs inhibit IL-10-producing B cells.


Ample evidence supports a protective role of iNKTs in inflammatory conditions [1721]. We have reported several lines of evidence suggesting a regulatory role of CD1d system in lupus. First, iNKTs inhibit autoreactive B cells [4]. Second, deficiency of CD1d exacerbates lupus dermatitis [22], whereas αGalCer treatment ameliorates dermatitis in the MRL-lpr model [16]. Third, CD1d deficiency exacerbates lupus induced by hydrocarbon oil tetramethylpentadecane (TMPD) [15], whereas αGalCer treatment ameliorates TMPD-induced lupus in BALB/c mice [23]. Fourth, CD1d deficiency worsens lupus nephritis in BWF1 mice [5]. Consistently, aged Jα18-deficient mice develop antibodies against double-stranded DNA and features of immune nephritis [24]. A suppressive role for iNKTs was also reported in a model where autoantibody production is triggered by an increased load of circulating apoptotic cells [6]. Contrary to these observations supporting a protective role of CD1d-reactive T cells in lupus, other reports showed that an anti-CD1d antibody prevents lupus [25], and αGalCer treatment worsens it in BWF1 mice [26, 27]. Analogously, treatment with an anti-CD1d antibody reduces collagen-induced arthritis [28], whereas iNKT activation protects against arthritis [19, 29]. Such paradoxical observations prompted us to further probe the role of iNKTs in lupus.

In this study, a brief treatment with αGalCer conferred a long-term protection against lupus in BWF1 mice. Long-term repeated administrations of αGalCer, however, had no significant effect on disease. Our data offer a potential mechanism to explain such disparate effects of iNKT activation on lupus disease. We show that a brief exposure to αGalCer boosts iNKT response in BWF1 mice. Such transient restoration of iNKT responses appears to re-set the autoimmune process, conferring long-term protection against lupus. Upon a prolonged and repetitive exposure to the same glycolipid antigen (αGalCer), however, iNKTs undergo profound hyporesponsiveness, which correlates with a lack of therapeutic benefit to αGalCer in BWF1 mice. Further studies are needed to critically link iNKT cell responsiveness to clinical effects in lupus, especially as to when or after how many injections of αGalCer the iNKT cell hyporesponsiveness sets in.

The therapeutic benefit of short-term iNKT activation in conferring protection has been reported in animal models of collagen-induced arthritis, autoimmune encephalomyelitis (EAE), and bronchial asthma [1921, 30]. In an animal model of asthma, a single subcutaneous injection of αGalCer at the time of intranasal antigen challenge abrogates disease, while continuous αGalCer administrations increase disease [20, 21]. In EAE, a single αGalCer injection prior to induction of disease prevents it, but enhances disease when injected at the time of disease induction [30]. In BWF1 mice, initiating αGalCer treatment at 20 weeks of age when mice already have disease modestly accelerated 50% prevalence of moderate (2+) proteinuria by ~7 weeks [26]. Thus, the timing of treatment in relation to the stage of disease and the route and frequency of administration of glycolipid antigens may all influence its therapeutic efficacy in inflammatory diseases [31].

In a previous study, whereas αGalCer treatment suppressed TMPD-induced renal disease in BALB/c mice, it increased renal disease in SJL mice [23]. Similarly, αGalCer can prevent EAE in B10.PL, PL/J, and C57BL/6 mice [30, 32, 33], but had little effect, or even exacerbated disease in a relapsing–remitting model of EAE in SJL mice [33]. Furthermore, iNKTs can modulate certain disease manifestations, but not others, in the same animal strain. For example, αGalCer treatment and CD1d deficiency modulate dermatitis, but not nephritis, in the MRL-lpr model [16, 22]. Delineating mechanisms underlying these divergent effects of iNKTs in different models of inflammatory diseases will help pave the way for iNKT-based therapies in humans.

It is unclear how iNKTs might regulate autoimmune diseases. We have recently reported that iNKTs inhibit CD1dhi autoreactive B cells and reduce the number of IL-10-secreting B cells in vitro [4]. In this study, we show that IL-10 production by spleen cells was reduced in αGalCer-treated mice. The reduced IL-10 production is not likely owing to αGalCer-induced clinical effect, as iNKTs reduced IL-10-secreting cells in vivo in the reconstituted SCID mice and in vitro in co-cultures of purified iNKT and B cells. Our finding is likely important, because autoreactive B cells from patients with SLE produce increased amounts of IL-10 [34]. We have also recently shown that anti-DNA B cells spontaneously express higher levels of IL-10 than non-anti-DNA B cells [4]. In vivo neutralization of IL-10 reduces autoantibody production in reconstituted hu-SCID mice [34] and suppresses nephritis in BWF1 mice [35]. A pilot trial of an anti-IL-10 mAb also showed reduced disease activity in SLE patients [36]. Thus, the ability of iNKT cells to regulate IL-10-producing B cells might underlie their capacity to suppress lupus. In EAE, however, IL-10 plays a role in iNKT cell-mediated protection from autoimmune disease [33], suggesting that different mechanisms may underlie iNKT cell effects in different inflammatory diseases.

Given the limited polymorphic nature of CD1 genes with ensuing therapeutic advantage over highly polymorphic MHC class I and class II systems, there has been a tremendous interest in understanding iNKT biology in inflammatory diseases. Results of this study link the clinical effect of treatment with an iNKT ligand to iNKT responsiveness. Enhanced iNKT responsiveness after a brief treatment correlates with protection from disease, whereas reduced iNKT responsiveness after a prolonged treatment correlates with a lack of therapeutic effect. We further suggest a mechanism whereby iNKTs might protect against lupus by suppressing IL-10 production. These data have important implications for the development of new avenues to prevent relapses in autoimmune diseases.


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).

Contributor Information

Jun-Qi Yang, 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. University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu, China.

Peter J. Kim, 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.

Ram Raj Singh, 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. University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA 90095, USA. Jonsson Comprehensive Cancer Center, UCLA, 1000 Veteran Avenue, Room 32-59 Rehab Center, Los Angeles, CA 90095-1670, USA, ude.alcu.tendem@hgniSRR..


1. Bendelac A. CD1: presenting unusual antigens to unusual T lymphocytes. Science. 1995;269:185–186. [PubMed]
2. Godfrey DI, MacDonald HR, Kronenberg M, Smyth MJ, Van Kaer L. NKT cells: what's in a name? Nat Rev Immunol. 2004;4:231–237. [PubMed]
3. Kronenberg M. Toward an understanding of NKT cell biology: progress and paradoxes. Annu Rev Immunol. 2005;23:877–900. [PubMed]
4. Yang JQ, Wen X, Kim PJ, Singh RR. Invariant NKT cells inhibit autoreactive B cells in a contact- and CD1d-dependent manner. J Immunol. 2011;186:1512–1520. [PMC free article] [PubMed]
5. Yang JQ, Wen X, Liu H, Folayan G, Dong X, Zhou M, et al. Examining the role of CD1d and natural killer T cells in the development of nephritis in a genetically susceptible lupus model. Arthritis Rheum. 2007;56:1219–1233. [PMC free article] [PubMed]
6. Wermeling F, Lind SM, Jordo ED, Cardell SL, Karlsson MC. Invariant NKT cells limit activation of autoreactive CD1d-positive B cells. J Exp Med. 2010;207:943–952. [PMC free article] [PubMed]
7. Wither J, Cai YC, Lim S, McKenzie T, Roslin N, Claudio JO, et al. Reduced proportions of natural killer T cells are present in the relatives of lupus patients and are associated with autoimmunity. Arthritis Res Ther. 2008;10:R108. [PMC free article] [PubMed]
8. Kojo S, Adachi Y, Keino H, Taniguchi M, Sumida T. Dysfunction of T cell receptor AV24AJ18+, BV11+ double-negative regulatory natural killer T cells in autoimmune diseases. Arthritis Rheum. 2001;44:1127–1138. [PubMed]
9. van der Vliet HJ, von Blomberg BM, Nishi N, Reijm M, Voskuyl AE, van Bodegraven AA, et al. Circulating V(alpha24+) Vbeta11 + NKT cell numbers are decreased in a wide variety of diseases that are characterized by autoreactive tissue damage. Clin Immunol. 2001;100:144–148. [PubMed]
10. Oishi Y, Sumida T, Sakamoto A, Kita Y, Kurasawa K, Nawata Y, et al. Selective reduction and recovery of invariant Vα24 JαQ T cell receptor T cells in correlation with disease activity in patients with systemic lupus erythematosus. J Rheumatol. 2001;28:275–283. [PubMed]
11. Hahn BH, Singh RR. Animal models of systemic lupus erythematosus. In: Wallace DJ, Hahn BH, editors. Dubois' lupus erythematosus, Lippincott. Philadelphia: Williams and Wilkins; 2007. pp. 299–355.
12. Bendelac A, Hunziker RD, Lantz O. Increased interleukin 4 and immunoglobulin E production in transgenic mice overexpressing NK1 T cells. J Exp Med. 1996;184:1285–1293. [PMC free article] [PubMed]
13. Cui J, Shin T, Kawano T, Sato H, Kondo E, Toura I, et al. Requirement for Vα14 NKT cells in IL-12-mediated rejection of tumors. Science. 1997;278:1623–1626. [PubMed]
14. Fan GC, Singh RR. Vaccination with minigenes encoding V(H)- derived major histocompatibility complex class I-binding epitopes activates cytotoxic T cells that ablate autoantibody-producing B cells and inhibit lupus. J Exp Med. 2002;196:731–741. [PMC free article] [PubMed]
15. Yang JQ, Singh AK, Wilson MT, Satoh M, Stanic AK, Park JJ, et al. Immunoregulatory role of CD1d in the hydrocarbon oilinduced model of lupus nephritis. J Immunol. 2003;171:2142–2153. [PubMed]
16. Yang JQ, Saxena V, Xu H, Van Kaer L, Wang CR, Singh RR. Repeated alpha-galactosylceramide administration results in expansion of NK T cells and alleviates inflammatory dermatitis in MRL-lpr/lpr mice. J Immunol. 2003;171:4439–4446. [PubMed]
17. Van Kaer L. alpha-Galactosylceramide therapy for autoimmune diseases: prospects and obstacles. Nat Rev Immunol. 2005;5:31–42. [PubMed]
18. Major AS, Singh RR, Joyce S, Van Kaer L. The role of invariant natural killer T cells in lupus and atherogenesis. Immunol Res. 2006;34:49–66. [PMC free article] [PubMed]
19. Coppieters K, Van Beneden K, Jacques P, Dewint P, Vervloet A, Vander Cruyssen B, et al. A single early activation of invariant NK T cells confers long-term protection against collagen-induced arthritis in a ligand-specific manner. J Immunol. 2007;179:2300–2309. [PubMed]
20. Dombrowicz D. Exploiting the innate immune system to control allergic asthma. Eur J Immunol. 2005;35:2786–2788. [PubMed]
21. Morishima Y, Ishii Y, Kimura T, Shibuya A, Shibuya K, Hegab AE, et al. Suppression of eosinophilic airway inflammation by treatment with alpha-galactosylceramide. Eur J Immunol. 2005;35:2803–2814. [PubMed]
22. Yang JQ, Chun T, Liu H, Hong S, Bui H, Van Kaer L, et al. CD1d deficiency exacerbates inflammatory dermatitis in MRL-lpr/lpr mice. Eur J Immunol. 2004;34:1723–1732. [PMC free article] [PubMed]
23. Singh AK, Yang JQ, Parekh VV, Wei J, Wang CR, Joyce S, et al. The natural killer T cell ligand alpha-galactosylceramide prevents or promotes pristane-induced lupus in mice. Eur J Immunol. 2005;35:1143–1154. [PMC free article] [PubMed]
24. Sireci G, Russo D, Dieli F, Porcelli SA, Taniguchi M, La Manna MP, et al. Immunoregulatory role of Jalpha281 T cells in aged mice developing lupus-like nephritis. Eur J Immunol. 2007;37:425–433. [PubMed]
25. Zeng D, Lee MK, Tung J, Brendolan A, Strober S. Cutting edge: a role for CD1 in the pathogenesis of lupus in NZB/NZW mice. J Immunol. 2000;164:5000–5004. [PubMed]
26. Zeng D, Liu Y, Sidobre S, Kronenberg M, Strober S. Activation of natural killer T cells in NZB/W mice induces Th1-type immune responses exacerbating lupus. J Clin Invest. 2003;112:1211–1222. [PMC free article] [PubMed]
27. Morshed SR, Takahashi T, Savage PB, Kambham N, Strober S. Beta-galactosylceramide alters invariant natural killer T cell function and is effective treatment for lupus. Clin Immunol. 2009;132:321–333. [PMC free article] [PubMed]
28. Chiba A, Kaieda S, Oki S, Yamamura T, Miyake S. The involvement of V(alpha)14 natural killer T cells in the pathogenesis of arthritis in murine models. Arthritis Rheum. 2005;52:1941–1948. [PubMed]
29. Chiba A, Oki S, Miyamoto K, Hashimoto H, Yamamura T, Miyake S. Suppression of collagen-induced arthritis by natural killer T cell activation with OCH, a sphingosine-truncated analog of alpha-galactosylceramide. Arthritis Rheum. 2004;50:305–313. [PubMed]
30. Jahng AW, Maricic I, Pedersen B, Burdin N, Naidenko O, Kronenberg M, et al. Activation of natural killer T cells potentiates or prevents experimental autoimmune encephalomyelitis. J Exp Med. 2001;194:1789–1799. [PMC free article] [PubMed]
31. Van Kaer L. Natural killer T cells as targets for immunotherapy of autoimmune diseases. Immunol Cell Biol. 2004;82:315–322. [PubMed]
32. Furlan R, Bergami A, Cantarella D, Brambilla E, Taniguchi M, Dellabona P, et al. Activation of invariant NKT cells by alphaGalCer administration protects mice from MOG35-55- induced EAE: critical roles for administration route and IFNgamma. Eur J Immunol. 2003;33:1830–1838. [PubMed]
33. Singh AK, Wilson MT, Hong S, Olivares-Villagomez D, Du C, Stanic AK, et al. Natural killer T cell activation protects mice against experimental autoimmune encephalomyelitis. J Exp Med. 2001;194:1801–1811. [PMC free article] [PubMed]
34. Llorente L, Zou W, Levy Y, Richaud-Patin Y, Wijdenes J, Alcocer-Varela J, et al. Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus. J Exp Med. 1995;181:839–844. [PMC free article] [PubMed]
35. Ishida H, Muchamuel T, Sakaguchi S, Andrade S, Menon S, Howard M. Continuous administration of anti-interleukin 10 antibodies delays onset of autoimmunity in NZB/W F1 mice. J Exp Med. 1994;179:305–310. [PMC free article] [PubMed]
36. Llorente L, Richaud-Patin Y, Garcia-Padilla C, Claret E, Jakez-Ocampo J, Cardiel MH, et al. Clinical and biologic effects of anti-interleukin-10 monoclonal antibody administration in systemic lupus erythematosus. Arthritis Rheum. 2000;43:1790–1800. [PubMed]
PubReader format: click here to try


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...