Intravenous immune globulin affects cytokine production in T lymphocytes and monocytesjmacrophages

Abstract

Summary Immune globulin for intravenous use (IVIG) has been used in many inflammatory conditions due to its immunomodulatory potential. The effector mechanisms are incompletely understood. This study dealt with the effects of IVIG on cytokine production in vitro. Cytokine synthesis was identified at the single-cell level using cytokine-specific MAb and indirect immunocytochemical techniques. Peripheral blood mononuclear cells (PBMC) were stimulated for 96 h by immobilized anti-CD3 MAb or by a combination of a protein kinase C activator (PMA) and a calcium ionophore (ionomycin). The addition of IVIG (6 mg/ml) caused a marked inhibition of proliferation and blast transformation despite unaffected cell survival. Anti-CD3-stimulatcd cultures containing IVIG exhibited a significant inhibition of production of T-cell derived lymphokines IL-2, IL-10, TNF-β, IFN-1 and TNF-α (made by both monocytes and T cells), while synthesis of the monokinc IL-8 was significantly increased. The expression of IL-2 receptors was significantly suppressed. Similar but transient inhibition of most T-cell products (IL-2, IL-3, IL-4, IL-5, IL-10, TNF-β and GM-CSF) was noted in the PMA/ionomycin-containing cultures. In contrast, no effects were found on IFN-γ or TNF-α production. The supcrantigen streptococcal pyrogenic exotoxin-A (SPE-A) induced vigorous cell activation and extensive cytokine synthesis. IVIG was added either at the beginning or 24 h after the initiation of cultures in order to elucidate the importance of direct toxinneutralization. Addition of IVIG from the beginning of cultures induced a strong reduction of blast transformation and an almost complete inhibition of lymphokinc production, in particular of IFN-γ and TNF-β. Supplementation with IVIG 24 h after initiation of cultures also led to a significant decrease in lymphokine synthesis. Monokine production (IL-1α, IL-1β, IL-lra, IL-6 and IL-8) was either unaffected or even increased. These two facts argue against direct antigen-neutralization as being the only mechanism at work. However, in IVIG-exposed PBMC stimulated with LPS, IL-6 production was significantly r,educed. A significant upregulation of IL-lra was noticed in unstimulated PBMC cultured with IVIG. The results in all the experiments did not indicate a cytotoxic effect by IVIG on cell survival and the production of certain cytokines were unaffected. Instead, the authors believe that the results suggest a previously little examined functional link where the humoral immune response may have direct immunoregulatory effects on the cellular immune system.