Repeated α-Galactosylceramide Administration Results in Expansion of NK T Cells and Alleviates Inflammatory Dermatitis in MRL-<i>lpr/lpr</i> Mice

Yang, Jun; Saxena, Vijay; Xu, Hui; Kaer, Luc Van; Wang, Chyung Ru; Singh, Ram Raj

doi:10.4049/jimmunol.171.8.4439

Cited by 117 publications

(125 citation statements)

References 34 publications

(57 reference statements)

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“…Indeed, treatment with § -galactosylceramide, which results in the expansion and activation of CD1d-reactive NKT cells, alleviates dermatitis in MRL-lpr mice [14]. Humans with SLE and other systemic autoimmune diseases also have reduced numbers of NKT cells, and disease activity in patients with SLE appears to inversely correlate with circulating NKT cell numbers [17][18][19].…”

Section: Discussionmentioning

confidence: 99%

“…Since repeated activation of CD1d-reactive NKT cells can alter the overall cytokine balance towards a type 2 cytokine profile in MRL-lpr mice [14], the lack of such cells in CD1d KO mice may result in decreased type 2 and/or increased type 1 immune responses. Indeed, while the production of the type 1 cytokine IFN-+ by Con A-stimulated splenic T cells was slightly increased, the type 2 cytokines IL-4 and IL-10 were significantly decreased in CD1d KO mice as compared to WT animals (Fig.…”

Section: Decreased Type 2 Cytokines (Il-4 and Il-10) In Cd1d Ko Mrl-lmentioning

confidence: 99%

“…Inflammatory skin lesions on the forehead, ears and dorsum of the neck [3,4,14] were scored on a scale of 0-3, where 0= no visible skin changes, 1= minimal hair loss with redness and a few scattered lesions, 2= redness, scabbing and hair loss with a small area of involvement and 3= ulcerations with an extensive area of involvement. For histology, skin biopsies from the back of neck were stored in 4% paraformaldehyde and sectioned.…”

Section: Assessment Of Skin Diseasementioning

confidence: 99%

“…A third possibility is that a deficiency in regulatory CD1d-dependent natural killer T (NKT) cells is responsible for the increased skin disease in g 2m-deficient MRL-lpr mice. In fact, MRL-lpr mice exhibit a selective reduction in the numbers and functions of invariant (V § 14J § 18) NKT cells before the onset of clinical disease [14]. Other studies have also found a specific decrease in the expression of invariant V § 14 TCR mRNA by NKT cells before the onset of disease in MRLlpr mice [15] and in the numbers of NK1.1-expressing cells in C57BL/6-lpr mice [16].…”

Section: Introductionmentioning

confidence: 99%

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CD1d deficiency exacerbates inflammatory dermatitis in MRL‐lpr/lpr mice

et al. 2004

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Mechanisms responsible for the development of autoimmune skin disease in humans and animal models with lupus remain poorly understood. In this study, we have investigated the role of CD1d, an antigen-presenting molecule known to activate natural killer T cells, in the development of inflammatory dermatitis in lupus-susceptible MRL-lpr/lpr mice. In particular, we have established MRL-lpr/lpr mice carrying a germ-line deletion of the CD1d genes. We demonstrate that CD1d-deficient MRL-lpr/lpr mice, as compared with wild-type littermates, have more frequent and more severe skin disease, with increased local infiltration with mast cells, lymphocytes and dendritic cells, including Langerhans cells. CD1d-deficient MRL-lpr/ lpr mice had increased prevalence of CD4 + T cells in the spleen and liver and of TCR § g + B220 + cells in lymph nodes. Furthermore, CD1d deficiency was associated with decreased T cell production of type 2 cytokines and increased or unchanged type 1 cytokines. These findings indicate a regulatory role of CD1d in inflammatory dermatitis. Understanding the mechanisms by which CD1d deficiency results in splenic T cell expansion and cytokine alterations, with increased dermal infiltration of dendritic cells and lymphocytes in MRL-lpr/lpr mice, will have implications for the pathogenesis of inflammatory skin diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Decreased Type 2 Cytokines (Il-4 and Il-10) In Cd1d Ko Mrl-lmentioning

confidence: 99%

Section: Assessment Of Skin Diseasementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CD1d deficiency exacerbates inflammatory dermatitis in MRL‐lpr/lpr mice

et al. 2004

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“…Conversely, the absence of NKT cells in CD1d-deficient NOD mice increases the incidence of diabetes (21,22). In MRL/lpr mice, invariant NKT cells are specifically reduced with aging (23), and repeated injections of ␣-GalCer prevent inflammatory dermatitis in these mice (24).…”

mentioning

confidence: 99%

Aberrant Genetic Control of Invariant TCR-Bearing NKT Cell Function in New Zealand Mouse Strains: Possible Involvement in Systemic Lupus Erythematosus Pathogenesis

Tsukamoto¹,

Ohtsuji²,

Shiroiwa

et al. 2008

The Journal of Immunology

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Both suppressive and promoting roles of NKT cells have been reported in the pathogenesis of systemic lupus erythematosus (SLE). Herein, we found that although New Zealand mice have normal frequencies of NKT cells, their in vitro potential to produce IL-4 and IFN-γ in response to α-galactosylceramide was remarkably impaired in New Zealand Black (NZB) mice prone to mild SLE, while production was highly up-regulated in nonautoimmune New Zealand White (NZW) mice and at intermediate levels in (NZB × NZW)F1 mice, which are prone to severe SLE. Because this aberration is evident in young mice before disease onset, genetic mechanisms are thought to be involved. Genome-wide quantitative trait locus analysis and association studies revealed that a locus linked to D11Mit14 on chromosome 11 may be involved in the difference in cytokine-producing potential between NZB and NZW NKT cells. Additionally, (NZB × NZW)F1 × NZB backcross progeny with the NZW genotype for D11Mit14 showed significantly increased frequencies of age-associated SLE phenotypes, such as high serum levels of IgG, IgG anti-DNA Abs, and lupus nephritis. In coculture studies, α-galactosylceramide-stimulated NKT cells from NZW and (NZB × NZW)F1 mice, but not from NZB mice, showed significantly enhanced Ig synthesis by B cells. These findings suggest that the D11Mit14-linked NZW locus may contribute to the development of SLE in (NZB × NZW)F1 mice through a mechanism that up-regulates NKT cell function. Thus, this NZW allele may be a candidate of the NZW modifiers that act to promote (NZB × NZW)F1 disease.

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Abrogation of skin disease in LUPUS‐prone MRL/FAS^lpr mice by means of a novel tylophorine analog

Choi¹,

Gao²,

Odegard³

et al. 2006

Arthritis & Rheumatism

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Objective. To test the therapeutic effect of DCB-3503, a synthetic compound derived from a natural product that inhibits NF-B, on end-organ disease in the MRL-Fas lpr murine model of systemic lupus erythematosus (SLE).Methods. Eight-week-old female MRL/Fas lpr mice were treated intraperitoneally with a low (2 mg/kg) or high (6 mg/kg) dose of DCB-3503 for 10 weeks. Control groups were administered vehicle treatment alone (negative control) or 25 mg/kg cyclophosphamide (positive control). Mice were bled before (8 weeks) and during (13 weeks) treatment, and when they were killed (20 weeks), and serum samples were analyzed for total IgM and IgG levels and autoantibody titers. When the mice were killed, spleen and lymph nodes (axillary, brachial, and cervical) were examined by flow cytometric analysis. The presence of skin and renal disease was determined by histopathologic analysis.Results. DCB-3503 reduced anti-double-stranded DNA and antichromatin autoantibodies and nearly abrogated inflammatory skin disease in MRL/Fas lpr mice; however, it had little effect on histologic kidney disease. Treated mice did not have hematologic or hepatic toxicity. These data indicate that end-organ disease in MRL/Fas lpr mice responds differentially to NF-B inhibitor.Conclusion. DCB-3503 causes significant abrogation of skin disease in MRL/Fas lpr mice and may potentially be beneficial in the treatment of inflammatory skin disease in SLE.

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Repeated α-Galactosylceramide Administration Results in Expansion of NK T Cells and Alleviates Inflammatory Dermatitis in MRL-lpr/lpr Mice

Cited by 117 publications

References 34 publications

CD1d deficiency exacerbates inflammatory dermatitis in MRL‐lpr/lpr mice

CD1d deficiency exacerbates inflammatory dermatitis in MRL‐lpr/lpr mice

Aberrant Genetic Control of Invariant TCR-Bearing NKT Cell Function in New Zealand Mouse Strains: Possible Involvement in Systemic Lupus Erythematosus Pathogenesis

Abrogation of skin disease in LUPUS‐prone MRL/FAS^lpr mice by means of a novel tylophorine analog

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Repeated α-Galactosylceramide Administration Results in Expansion of NK T Cells and Alleviates Inflammatory Dermatitis in MRL-lpr/lpr Mice

Cited by 117 publications

References 34 publications

CD1d deficiency exacerbates inflammatory dermatitis in MRL‐lpr/lpr mice

CD1d deficiency exacerbates inflammatory dermatitis in MRL‐lpr/lpr mice

Aberrant Genetic Control of Invariant TCR-Bearing NKT Cell Function in New Zealand Mouse Strains: Possible Involvement in Systemic Lupus Erythematosus Pathogenesis

Abrogation of skin disease in LUPUS‐prone MRL/FASlpr mice by means of a novel tylophorine analog

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Abrogation of skin disease in LUPUS‐prone MRL/FAS^lpr mice by means of a novel tylophorine analog