Administration of intravenous immunoglobulin (IVIG) in vivo--down-regulatory effects on the IL-1 system

Abstract

Modulation of the cytokine network may be of importance for the beneficial effects of therapy with IVIG seen in a wide range of immune-mediated disorders. In the present study we investigate the effect of IVIG administration in vivo on the IL-1 system in 12 patients with primary hypogammaglobulinaemia. Before IVIG infusion these patients had significantly elevated levels of IL-1alpha and IL-1beta both in plasma and in supernatants from peripheral blood mononuclear cells (PBMC) compared with healthy controls. After one bolus infusion with IVIG (0.4 g/kg) we found a significant change in the profile of the components of the IL-1 system: a marked increase in levels of IL-1 receptor antagonist (IL-1Ra) and neutralizing antibodies against IL-1alpha, a moderate decrease in levels of IL-1alpha, IL-1beta and soluble (s) IL-1 receptor type I and a significant increase in sIL-1 receptor type II levels. These changes were found both in plasma and in PBMC isolated after IVIG administration. Furthermore, pooled serum obtained after IVIG infusion suppressed lipopolysaccharide- and staphylococcal enterotoxin B-stimulated, but not phorbol myristate acetate-stimulated, release of IL-1alpha and IL-1beta from PBMC isolated from healthy controls. Finally, these changes in circulating levels of various IL-1 modulators after IVIG infusion appeared to cause a significantly impaired ability of IL-1 to stimulate PBMC for tumour necrosis factor-alpha release. Our findings suggest that IVIG administration may not only down-regulate the activity in the IL-1 system, but also hamper IL-1 stimulation of PBMC.

Fig. 1

Plasma levels of IL-1α (a), IL-1β (b), sIL-1RI (c), sIL-1RII (d) and IL-1α antibodies (e) before and at various hours after IVIG infusion in vivo. The levels of neutralizing IL-1α antibodies are given as maximal binding capacity expressed as IgG-bound IL-1α (ng) per ml plasma (e). For plasma levels of IL-1α (a) and IL-1β (b), only patients with detectable levels at baseline (n = 8 and n = 6, respectively) are given in the figure. All patients with undetectable IL-1α and IL-1β levels before IVIG infusion had undetectable levels of these cytokines throughout the study period. Data are given as medians and 25th — 75th percentiles. *P < 0.05; **P < 0.01; ***P < 0.005 versus pre-infusion levels.

Fig. 2

The effect of pooled serum obtained before and after IVIG infusion on stimulated IL-1 levels in peripheral blood mononuclear cells (PBMC). The figure presents data analysing the effect of medium containing 20% of pooled serum from six healthy blood donors (control) and 20% of pooled serum from patients with primary hypogammaglobulinaemia obtained before (0 h) and 1 h and 20 h after IVIG infusion in vivo on phorbol myristate acetate (PMA; 100 ng/ml), staphylococcal enterotoxin B (SEB; 10 ng/ml) and lipopolysaccharide (LPS; 10 ng/ml) stimulated levels of IL-1α (supernatants (a) and cell lysates (b)) and IL-1β (supernatants (c) and cell lysates (d)) in PBMC from six healthy blood donors after culturing for 20 h in vitro. Data are given as medians and 25th — 75th percentiles. *P < 0.05; **P < 0.01 versus pooled serum obtained before IVIG infusion (0 h); †P < 0.5; ††P < 0.01 versus pooled serum from healthy controls.

Fig. 3

The effect of medium containing 20% of the IVIG preparation (final concentration 10 mg/ml) and 20% of pooled serum obtained before (0 h) and 1 h and 20 h after IVIG infusion in vivo in patients with primary hypogammaglobulinaemia on IL-1α- and IL-1β-stimulated release of tumour necrosis factor-alpha (TNF-α) in vitro from peripheral blood mononuclear cells (PBMC) in six healthy controls when added to cell cultures 2 h before IL-1 stimulation. For comparison, PBMC cultured in medium containing 20% AB⁺ serum are also shown. Data are given as medians and 25th — 75th percentiles. *P < 0.05 versus pooled serum obtained before IVIG infusion (0 h); †significantly decreased (P < 0.05) and ‡significantly increased (P < 0.05) versus AB⁺ serum.