Effects of Cyclosporin A on the Activation of Natural Killer T Cells Induced by ??-Galactosylceramide:

Background. Natural killer T (NKT) cells play crucial roles in preventing autoimmune diseases and inducing transplantation tolerance. We investigated whether cyclosporin A (CsA), which is generally used in clinical transplantation and autoimmune disease therapy, could modulate the NKT cell activation induced by alpha-galactosylceramide (alpha-GalCer) treatment. Methods. C57BL/6 (B6) mice were given daily intraperitoneal injections of CsA (30 or 50 mg/kg) from day - I and injected intravenously with alpha-GalCer (2 mu g/mouse) on day 0. The kinetics of NK1.1(+)CD3(+) or NK1.1(+)Thy1.2(+) cells in the liver and spleen were analyzed by flow cytometry. Apoptosis of NK1.1(+) CD3(+) cells, cytokine levels (interleukin [IL]-2, IL-4, IL-10 and interferon [IFN]-gamma) in the recipient serum and changes in dendritic cell activation in the spleen were analyzed. Results. In B6 mice treated with alpha-GalCer, NK1.1(+)CD(3+) cells rapidly decreased in both the liver and spleen, and repopulated to their normal levels by day four, while NK1.1(+)Thy1.2(+) cells rapidly decreased, expanded by day four and reduced to their normal level by day 15. When 136 mice were treated with alpha-GalCer plus 30 or 50 mg/kg CsA, NK1.1(+)CD3(+) or NK1.1(+) Thy1.2(+) cells were similarly decreased and then expanded via extensive proliferation by day seven or four, respectively. When 136 mice were treated with alpha-GalCer, substantial amounts of IL-2, IL-4 and IFN-gamma were produced, and the surface markers of dendritic cells were upregulated. However, these cytokine productions and maturation of dendritic cells were profoundly suppressed after treatment with alpha-GalCer and CsA. Apoptosis of NK1.1(+)CD3(+) cells was not affected in mice treated with alpha-GalCer or alpha-GalCer and CsA. Conclusions. CsA suppresses alpha-GalCer-induced cytokine productions and dendritic cell maturation of mouse NKT cells but does not decrease NK1.1(+)CD3(+) cells on day one. The modulation of NKT-mediated immunoregulatory functions by CsA requires careful consideration in clinical transplantation and autoimmune disease therapy.