INTRAVENOUS IMMUNE GLOBULIN HAS EFFECTS ON SUPERANTIGEN-INDUCED CYTOKINE SYNTHESIS

Increased incidences of invasive group A streptococcal infections occu rred in the Western Society in the 1980s, and the number of streptococ cal toxic shock syndrome (STSS) cases continue to rise. Among the hypo theses entertained to explain the pathogenesis of STSS has been the co ncept that streptococcal superantigens (Sags), including streptococcal pyrogenic exotoxins (SPEs), can trigger potent inflammatory responses and release of cytokines of TH1 type (TNF-alpha, IL-1, IFN-gamma and TNF-beta). These may mediate tissue damage, organ failure, and shock. Pooled human immune globulin G (IgG) preparations for intravenous admi nistration (ivIgG) have been used in many inflammatory conditions due to their immunomodulatory potential. The effector mechanisms are incom pletely understood. This study dealt with the effects of ivIgG on cyto kine production in vitro. Cytokine synthesis was identified at the sin gle-cell level using cytokine-specific monoclonal antibodies (mAb) and indirect immunocytochemical techniques. The superantigen streptococca l Pyrogenic exotoxin-A (SPE-A) induced vigorous cell activation and ex tensive cytokine synthesis, ivIgG was added either at the beginning or 24 h after the initiation of cultures of peripheral blood mononuclear cells (PBMNC) in order to elucidate the importance of direct toxin ne utralization. Addition of ivIg (6 mg/ml) from the beginning of culture s induced a strong reduction of blast transformation and an almost com plete inhibition of lymphokine production, in particular of IFN-gamma and TNF-beta. Supplementation of ivIgG 24 h after initiation of cultur es also led to a significant decrease in lymphokine synthesis. Monokin e production (IL-la, IL-1 beta, IL-1ra, IL-6 and IL-8) was either unaf fected or even increased. These two facts argue against direct antigen neutralization as being the only mechanism at work. Yet IL-6 producti on was significantly reduced in ivIgG-exposed PBMNC stimulated with li popolysaccharide (LPS). A significant upregulation of IL-8 and IL-1 re ceptor antagonist (IL-1ra) was noticed in unstimulated PBMNC cultured with ivIgG. The results in all the experiments did not indicate a cyto toxic effect by ivIgG since cell survival and the production of certai n cytokines were unaffected. Instead, we believe that the results sugg est a previously litte examined functional link where the humoral immu ne response may have direct immunoregulatory effects on the cellular i mmune system. Thus, ivIgG may be of clinical value in patients with ST S but less so in endotoxin-mediated shock.