INTRAVENOUS IMMUNE GLOBULIN AFFECTS CYTOKINE PRODUCTION IN T-LYMPHOCYTES AND MONOCYTES MACROPHAGES

Immune globulin for intravenous use (IVIG) has been used in many infla mmatory conditions due to its immunomodulatory potential. The effector mechanisms are incompletely understood. This study dealt with the eff ects of IVIG on cytokine production in vitro. Cytokine synthesis was i dentified at the single-cell level using cytokine-specific MAb and ind irect immunocytochemical techniques. Peripheral blood mononuclear cell s (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 ionoph ore (ionomycin). The addition of IVIG (6 mg/ml) caused a marked inhibi tion of proliferation and blast transformation despite unaffected cell survival. Anti-CD3-stimulated cultures containing IVIG exhibited a si gnificant inhibition of production of T-cell derived lymphokines IL-2, IL-10, TNF-beta, IFN-gamma and TNF-alpha (made by both monocytes and T cells), while synthesis of the monokine IL-8 was significantly incre ased. The expression of IL-2 receptors was significantly suppressed. S imilar but transient inhibition of most T-cell products (IL-2, IL-3, I L-4, IL-5, IL-10, TNF-beta and GM-CSF) was noted in the PMA/ionomycin- containing cultures. In contrast, no effects were found on IFN-gamma o r TNF-alpha production. The superantigen streptococcal pyrogenic exoto xin-A (SPE-A) induced vigorous cell activation and extensive cytokine synthesis. IVIG was added either at the beginning or 24 h after the in itiation of cultures in order to elucidate the importance of direct to xin-neutralization. Addition of IVIG from the beginning of cultures in duced a strong reduction of blast transformation and an almost complet e inhibition of lymphokine production, in particular of IFN-gamma and TNF-beta. Supplementation with IVIG 24 h after initiation of cultures also led to a significant decrease in lymphokine synthesis. Monokine p roduction (IL-1 alpha, IL-1 beta, IL-1ra, IL-6 and IL-8) was either un affected or even increased. These two facts argue against direct antig en-neutralization as being the only mechanism at work. However, in IVI G-exposed PBMC stimulated with LPS, IL-6 production was significantly reduced. A significant upregulation of IL-1ra was noticed in unstimula ted PBMC cultured with IVIG. The results in all the experiments did no t indicate a cytotoxic effect by IVIG on cell survival and the product ion 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 ef fects on the cellular immune system.