Effects of cyclosporin A on the activation of natural killer T cells induced by alpha-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 -1 and injected intravenously with alpha-GalCer (2 mug/mouse) on day 0. The kinetics of NK1.1CD3 or NK1.1Thy1.2 cells in the liver and spleen were analyzed by flow cytometry. Apoptosis of NK1.1CD3 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, NK1.1CD3 cells rapidly decreased in both the liver and spleen, and repopulated to their normal levels by day four, while NK1.1Thy1.2 cells rapidly decreased, expanded by day four and reduced to their normal level by day 15. When B6 mice were treated with alpha-GalCer plus 30 or 50 mg/kg CsA, NK1.1CD3 or NK1.1 Thy1.2cells were similarly decreased and then expanded via extensive proliferation by day seven or four, respectively. When B6 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 NK1.1CD3 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 NK1.1CD3 cells on day one. The modulation of NKT-mediated immunoregulatory functions by CsA requires careful consideration in clinical transplantation and autoimmune disease therapy.
Kajiwara
Takashi
T
Department of Cardiovascular Surgery, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Tomita
Yukihiro
Y
Okano
Shinji
S
Iwai
Toshiro
T
Yasunami
Youichi
Y
Yoshikai
Yasunobu
Y
Nomoto
Kikuo
K
Yasui
Hisataka
H
Tominaga
Ryuji
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D017252:CD3 Complex / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D005699:Galactosylceramides / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007700:Kinetics; D016031:Liver Transplantation / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D018655:Lymphocyte Count; D051379:Mice; D013154:Spleen / Q000276:immunology / Q000637:transplantation; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D013934:Thymectomy; D013997:Time Factors
D017252:CD3 Complex; D016207:Cytokines; D005699:Galactosylceramides; C493154:alpha-galactosylceramide; D016572:Cyclosporine