Suppression of skin and kidney disease by inhibition of spleen tyrosine kinase in lupus-prone mice - PubMed (original) (raw)

Suppression of skin and kidney disease by inhibition of spleen tyrosine kinase in lupus-prone mice

Guo-Min Deng et al. Arthritis Rheum. 2010 Jul.

Abstract

Objective: Spleen tyrosine kinase (Syk) is involved in membrane-mediated signaling in various cells, including immune cells. It is overexpressed in T cells from patients with systemic lupus erythematosus (SLE), and its inhibition has been shown to improve T cell function as well as to improve disease manifestations in (NZB x NZW)F(1) lupus-prone mice and in patients with rheumatoid arthritis. While clinical trials examining Syk inhibition in patients with SLE are being considered, the aim of our experiments was to determine whether the therapeutic effects of Syk inhibition extend to other strains of lupus-prone mice and whether they result in improvement in skin disease and modification of established disease.

Methods: Female MRL/lpr or BAK/BAX mice were studied. Starting either at age 4 weeks (before disease) or at age 16 weeks (after established disease) and continuing for up to 16 weeks, mice were fed chow containing the Syk inhibitor R788 or control chow.

Results: We found that inhibition of Syk in MRL/lpr and BAK/BAX mice prevented the development of skin disease and significantly reduced established skin disease. Similarly, Syk inhibition reduced the size of the spleen and lymph nodes, suppressed the development of renal disease, and suppressed established renal disease. Discontinuation of treatment resulted in extended suppression of skin disease for at least 8 weeks and suppression of renal disease for 4 weeks.

Conclusion: Syk inhibition suppresses the development of lupus skin and kidney disease in lupus-prone mice, suppresses established disease in lupus-prone mice, and may represent a valuable treatment for patients with SLE.

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Figures

Figure 1

Figure 1

Syk expression in the skin lesions of female MRL/lpr mice. A, Photograph showing representative skin lesions in MRL/lpr mice. B, Syk expression in skin lesions from MRL/lpr mice stained with anti-Syk antibody and isotype control. Syk is present in the epidermis as well as in the dermis-infiltrating inflammatory cells. Representative photomicrographs are shown (original magnification × •••).

Figure 2

Figure 2

Prevention of the development of skin lesions in female lupus-prone MRL/lpr mice by treatment with Syk inhibitor R788. A, Photograph showing representative MRL/lpr mice treated with R788 (3 gm/kg of chow) or control chow. B, Incidence and severity of skin lesions in MRL/lpr mice treated with R788 (3 gm/kg or 10 gm/kg of chow) or control chow. Values are the mean and SD of 8 mice per group. * = P < 0.01 versus control. C, Histopathologic features of skin lesions from MRL/lpr mice treated with R788 (3 gm/kg or 10 gm/kg of chow) or control chow. Representative photomicrographs are shown (original magnification × •••).

Figure 3

Figure 3

Marked improvement in established skin lesions in female lupus-prone MRL/lpr mice following treatment with Syk inhibitor R788. A, Incidence of skin lesions in MRL/lpr mice treated for 6 weeks with 3 gm of R788 per kg of chow starting at age 12 weeks, with 10 gm of R788 per kg of chow starting at age 16 weeks, or with control chow starting at age 12 weeks or 16 weeks. Values are the mean and SD of ••• mice per group. B, Severity and histopathologic features of skin lesions from MRL/lpr mice treated for 6 weeks with R788 (3 gm/kg of chow) or with control chow starting at age 12 weeks. Values are the mean and SD of ••• mice per group. * = P < 0.01 versus control. Representative photomicrographs are shown (original magnification × •••). C, Incidence of skin lesions at 14 weeks. Mice were treated for 6 weeks with Syk inhibitor and were then divided into 2 subgroups: one continued Syk inhibitor and the other received control chow for 8 weeks. The incidence of skin injury was then recorded. Values are the mean and SD of ••• mice per group.

Figure 4

Figure 4

Effects of Syk inhibitor R788 on kidney disease in female lupus-prone MRL/lpr mice. A, Levels of proteinuria and urinary leukocytes in MRL/lpr mice treated with R788 (3 gm/kg or 10 gm/kg of chow) or control chow. Values are the mean of ••• mice per group. B, Histopathologic features of kidney sections from MRL/lpr mice treated with R788 (3 gm/kg or 10 gm/kg of chow) or control chow. Representative photomicrographs are shown (original magnification × •••). C, Proteinuria in MRL/lpr mice treated for 6 weeks with R788 (10 gm/kg of chow) or control chow starting at the age of 16 weeks. Values are the mean of 4 mice per group.

Figure 5

Figure 5

Reduction of lymphadenopathy, splenomegaly, and thymus size in female lupus-prone MRL/lpr mice following treatment with Syk inhibitor R788. A, Representative photographs of lymph nodes, spleens, and thymuses from MRL/lpr mice treated with Syk inhibitor R788 (3 gm/kg or 10 gm/kg of chow) or control chow. B, Incidence of lymphadenopathy in MRL/lpr mice treated with 3 gm of R788 per kg of chow starting at age 12 weeks, with 10 gm of R788 per kg of chow starting at age 16 weeks, or with control chow starting at age 12 weeks or 16 weeks. Values are the mean and SD of 4 mice per group. C, Reduced numbers of dendritic cells in skin lesions of MRL/lpr mice following treatment with Syk inhibitor R788. Immunofluorescence staining of anti-CD11c expression in skin lesions from MRL/lpr mice treated for 16 weeks with 3 gm of R788 per kg of chow or with control chow starting at age 6 weeks. Representative photomicrographs are shown (original magnification × •••).

Figure 6

Figure 6

Improvement of skin lesions in female BAK/BAX double-deficient mice following treatment with Syk inhibitor R788. A, Incidence of skin lesions (left) and representative photograph showing the appearance of skin lesions (right) in BAK/BAX double-deficient mice treated for 12 weeks with 3 gm of R788 per kg of chow or with control chow starting at age 6 weeks. Values are the mean and SD of 4 mice per group. B, Histopathologic features of skin lesions from BAK/BAX double-deficient mice treated with 3 gm of R788 per kg of chow or with control chow. Representative photomicrographs are shown (original magnification × •••)

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