REDUCTION OF MORBIDITY AND CYTOKINE RELEASE IN ANTI-CD3... : Transplantation (original) (raw)

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REDUCTION OF MORBIDITY AND CYTOKINE RELEASE IN ANTI-CD3 MoAb-TREATED MICE BY CORTICOSTEROIDS

FERRAN, CHRISTIANE; DY, MICHEL; MERITE, SYLVIE; SHEEHAN, KATHLEEN; SCHREIBER, ROBERT; LEBOULENGER, FRANÇOIS; LANDAIS, PAUL; BLUESTONE, JEFFREY; BACH, JEAN-FRANÇOIS; CHATENOUD, LUCIENNE

Laboratoire de Biostatistique et d'Informatique Médicales and INSERM U 25

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Abstract

In keeping with the in vitro mitogenic properties of anti-CD3 MoAbs, the first injections of anti-CD3 are invariably responsible for an in vivo cellular activation. This activation induces a massive cytokine release in the circulation (TNF, IFNγ, IL-2, IL-6, and IL-3). Paralleling this release, a severe clinical reaction occurs in OKT3-treated patients and in 145 2C11-treated mice. Corticosteroids both in vitro and in vivo inhibit the production of several cytokines involved in the anti-CD3 reaction. A single 1 mg hydrocortisone dose was administered to 145 2C11-treated mice according to different kinetics schedules. When given 1 hr prior to the anti-CD3 MoAb, hydrocortisone exerted a beneficial effect on the mouse physical reaction. Hypothermia was totally abrogated at the 4-hr time point. Diarrhea decreased by 50%. Hypomotility improved although not significantly. This improvement correlated with a major modification in the anti-CD3 pattern of cytokine release. At the 90-min blood withdrawal time point cytokine serum levels showed a 100% decrease for IFNγ, an 88% decrease for IL-6, an 85% decrease for IL-2, and a 75% decrease for TNF. At 4 hr IL-2 serum levels were diminished by 65%; IL-6, IL-3, and IFNγ serum levels were comparable to controls; and, interestingly, TNF was still detected, whereas it has already disappeared when 145 2C11 was administered alone. Importantly, when given more than 1 hr prior to anti-CD3 injection, corticosteroids were ineffective. To conclude, high doses of corticosteroids must be given with a precise kinetics

i.e. 1 hr prior to anti-CD3 MoAb to achieve their maximal beneficial effect in the prevention of the anti-CD3 reaction.