Interference with CD28, CD80, CD86 or CD152 in collagen-induced arthritis. Limited role of IFN-gamma in anti-B7-mediated suppression of disease.

We have investigated interference with co-stimulation by administering mAbs towards CD28, CD80, CD86, and CD152 in mice immunized for the development of collagen-induced arthritis (CIA). Anti-CD80 and anti-CD86 treatment inhibited disease score and incidence, whereas anti-CD28 treatment led only to a delayed disease onset. Administration of anti-CD152 had no effect. The CII-specific Ab-response was suppressed by the co-stimulatory blockade, with a stronger effect on IgG1 than on IgG2a. The CII-driven T cell proliferation, on the other hand, was not affected. Furthermore, T cells primed in the presence of either anti-B7 or anti-CD28 produced markedly increased amounts of IFN-gamma in response to CII. To investigate whether this increase in IFN-gamma was related to disease suppression, IFN-gamma-deficient mice were immunized with CII, treated with anti-B7 and followed for the development of arthritis. As in the wild-type mice, administration of anti-B7 to IFN-gamma-deficient mice led to a reduced disease incidence and severity as well as reduced anti-CII IgG titers. Collectively, these data stress the importance of co-stimulation for the delivery of B cell help rather than for production of Th1 cytokines. We also demonstrate that the enhanced production of IFN-gamma observed after B7-blockade is not accountable for the anti-B7 mediated inhibition of CIA.

Prolonged airway activity and improved selectivity of budesonide possibly due to esterification.

We addressed the question of whether the prolonged local retention of the glucocorticoid (GC) budesonide (BUD) within airway tissue, due to reversible fatty acid esterification, is associated with protracted topical anti-inflammatory activity and improved airway selectivity, when compared with fluticasone propionate (FP). BUD or FP at 25 nmol/kg was administered intratracheally or subcutaneously to adrenalectomized rats, followed by lipopolysaccharide (LPS) intratracheal instillation. The trachea and main bronchi were lavaged 6 h after LPS, and tumor necrosis factor-alpha (TNF-alpha) concentration and cell number in the lavage fluid were measured. Instilled 1 h before LPS, both GCs reduced TNF-alpha by 70% (p < 0.05) and mononuclear cells by 55% (p < 0.01), with no reduction in neutrophils. Instilled 6 h before LPS, a significant reduction of TNF-alpha (59%, p < 0.02) and mononuclear cells (47%, p < 0.05) was achieved only with BUD. After subcutaneous administration, no significant effects were observed. BUD did not exert higher systemic activity than FP, measured as plasma corticosterone suppression. In conclusion, BUD exerted a more prolonged topical anti-inflammatory activity, and a higher airway selectivity than FP, possibly because of its reversible fatty acid esterification within airway tissue. This may contribute to the high efficacy and safety of BUD in asthma, even with once-daily inhalation.

Adrenalectomy permits a late, local TNF-alpha release in LPS-challenged rat airways.

The normal rise of circulating endogenous glucocorticosteroids (GCS), in response to immunological stimuli, can be impaired in patients with inflammatory diseases. The aim of this study was to investigate whether abolition of the endogenous GCS response promotes local production of the pro-inflammatory cytokine, tumour necrosis factor (TNF)-alpha, in challenged airways and affects the cellular response in rats. In adrenalectomized or sham operated rats, the trachea and main bronchi were lavaged at various times after intratracheal instillation of low dose lipopolysaccharide (LPS). TNF-alpha in lavage fluid and plasma corticosterone were measured, and cells were differentiated. In adrenalectomized rats, LPS-induced in the airways a biphasic TNF-alpha release peaking at 2 and 6 h, whereas in sham operated rats the second peak was absent; probably inhibited by the strong rise of plasma corticosterone. The second peak was abolished in adrenalectomized rats by pretreatment with exogenous GCS. The LPS-induced neutrophil influx and a decrease in mononuclear cells were prolonged in adrenalectomized rats. In conclusion, abolition of the endogenous glucocorticosteroid response promotes the late release of tumour necrosis factor-alpha in the airways and prolongs the cellular response. This suggests that a normal rise of endogenous glucocorticosteroid after an immunological trigger contributes to a dampening of the late inflammatory activity.