THERAPEUTIC PREPARATIONS OF NORMAL POLYSPECIFIC IGG (IVIG) INDUCE APOPTOSIS IN HUMAN-LYMPHOCYTES AND MONOCYTES - A NOVEL MECHANISM OF ACTION OF IVIG INVOLVING THE FAS APOPTOTIC PATHWAY

Therapeutic preparations of normal human IgG far i.v. use (IVIg) exhib it a broad spectrum of immunoregulatory activities in vitro and in viv o. IVIg has been shown to inhibit the proliferation of activated B and T lymphocytes and of several autonomously growing cell lines. In this study, we demonstrate that IVIg induces apoptosis in leukemic cells o f lymphocyte and monocyte lineage and in CD40-activated normal tonsill ar B cells, involving, at least in part, Pas (CD95/APO-1) and activati on of caspases, IVIg-induced apoptosis was higher in Fas-sensitive HuT 78 cells than in Fas-resistant HuT78.B1 mutant cells, and soluble Fas inhibited IVIg-induced apoptosis, IVIg immunoprecipitated Fas from Fas -expressing transfectants and recognized purified Fas/glutathione-S-tr ansferase fusion proteins upon immunoblotting, Affinity-purified anti- Fas Abs from IVIg induced apoptosis of CEM T cells at a 120-fold lower concentration than unfractionated IVIg, Inhibitors of cysteine protea ses of the caspase family, caspase 1 (IL-1 beta-converting enzyme) and caspase 3 (Yama/CPP32b), partially inhibited IVIg-induced apoptosis o f CEM cells, Furthermore, cleavage of poly(A)DP-ribose polymerase into an 85-kDa signature death fragment was observed in CEM cells followin g IVIg treatment. Thus, normal IgG induces apoptosis in lymphocytes an d monocytes. Our results provide evidence for a role of Fas, bring new insights into the mechanisms of action of IVIg in autoimmune diseases , and suggest a role of normal Ig in controlling cell death and prolif eration.