Modulation of the release of cytokines and reduction of the shock syndrome induced by anti-CD3 monoclonal antibody in mice by interleukin-10.
Since IL-10 was recently shown to inhibit several T cell functions in vitro, we investigated the effects of IL-10 on the cytokine release syndrome induced in mice by the 145-2C11 anti-CD3 mAb. As OKT3 in man, this mAb induces a massive polyclonal T cell activation before to induce immunosuppression. First, we found that administration of 1000 U of recombinant mouse IL-10 (mIL-10) 30 min before injection of 10 micrograms of the 145-2C11 antimouse CD3 mAb markedly reduced the systemic release of IFN-gamma and TNF. In contrast, IL-10 pretreatment did not significantly modify the release of IL-6. To determine the effect of IL-10 pretreatment on the endogenous secretion of IL-10 induced by the 145-2C11 mAb, mice were injected with human IL-10 (hIL-10) which does not cross-react in the ELISA for mIL-10 determination. While hIL-10 was as efficient as mIL-10 in reducing TNF and IFN-gamma release, it did not modify peak serum levels of IL-10. The modulation of cytokine production by mIL-10 was associated with a significant reduction of the toxicity of the 145-2C11 mAb, as assessed by the attenuation of hypothermia and by the reduced lethality in D-galactosamine-sensitize mice. We conclude that IL-10 differentially regulates the in vivo production of cytokines and decreases the systemic toxicity induced by the 145-2C11 mAb. These observations suggest potential therapeutic applications of IL-10 in organ transplantation, especially in association with anti-CD3 mAb.
Donckier
V
V
Département de Biologie Moléculaire, Université Libre de Bruxelles, Belgium.
Flament
V
V
Gérard
C
C
Abramowicz
D
D
Vandenabeele
P
P
Wissing
M
M
Delvaux
A
A
Fiers
W
W
Leo
O
O
Velu
T
T
D000818:Animals; D000911:Antibodies, Monoclonal; D017252:CD3 Complex / Q000276:immunology*; D016572:Cyclosporine / Q000494:pharmacology; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D012636:Secretory Rate / Q000187:drug effects; D012769:Shock / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma; D016572:Cyclosporine