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Type 1 regulatory T cells in treatment of murine lupus

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Systemic lupus erythematosus is a severe systemic autoimmune disease characterized by loss of tolerance towards a restricted panel of autoantigens. As a result, pathogenic autoantibodies against dsDNA or the Sm proteins occur. We identified the SmD1(83-119) peptide, the C-terminus of the spliceosomal protein SmD1, as a major B-cell and T-cell autoantigen in human and murine lupus [13]. In previous work we could show that intravenous high-dose application of SmD1(83-119) prolongs survival in NZB/W F1 mice and delays occurrence of anti-dsDNA autoantibodies [4]. Higher percentages of CD4+ T cells that produce IL-10 and interferon gamma were detected on restimulation with phorbol 12-myristate 13-acetate/ionomycin later on in the spleen, indicating involvement of type 1 regulatory T cell (Tr1 cell)-mediated tolerance [4]. Transfer of splenic CD90+ T cells from mice treated with high doses of SmD1(83-119) into untreated mice delayed the occurrence of anti-dsDNA autoantibodies in these recipients as well [4].

We now performed a SmD1(83-119) specific analysis of the CD4+ T cells after high-dose application of SmD1(83-119) and detected SmD1(83-119)-reactive CD4+IL-10+ Tr1 cells in the spleen and in draining lymph nodes after additional immunization with SmD1(83-119). In vitro experiments showed that Tr1-cell-mediated suppression of anti-DNA autoantibody production is dependent on the activity of IL-10 as the addition of neutralizing anti-IL-10 antibodies abrogated this effect. Furthermore, adoptive transfer of SmD1(83-119) reactive Tr1-cell-containing lymph node cells delayed the occurrence of anti-DNA autoantibodies in the recipient mice as well.

We conclude that high-dose application of SmD1(83-119) induces SmD1(83-119) specific tolerance in NZB/W F1 mice, which is mediated by SmD1(83-119)-reactive Tr1 cells. These results may open new ways for future autoantigen specific cell-based therapies in systemic lupus erythematosus.

References

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    Riemekasten G, et al: A novel epitope on the C-terminus of SmD1 is recognized by the majority of sera from patients with systemic lupus erythematosus. J Clin Invest. 1998, 102: 754-763.

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    Riemekasten G, et al: T cell reactivity against the SmD1(83-119) C terminal peptide in patients with systemic lupus erythematosus. Ann Rheum Dis. 2002, 61: 779-785. 10.1136/ard.61.9.779.

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    Riemekasten G, et al: Identification and characterization of SmD183-119-reactive T cells that provide T cell help for pathogenic anti-double-stranded DNA antibodies. Arthritis Rheum. 2003, 48: 475-485. 10.1002/art.10762.

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    Riemekasten G, Langnickel D, et al: Intravenous injection of a D1 protein of the smith proteins postpones murine lupus and induces type 1 regulatory T cells. J Immunol. 2004, 173: 5835-5842.

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Acknowledgements

RU and JH contributed equally to this work.

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Keywords

  • Systemic Lupus Erythematosus
  • Lymph Node Cell
  • Systemic Autoimmune Disease
  • Specific Tolerance
  • Splenic CD90