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*
Institut National de la Santé et de la Recherche Médicale U430, and Université Pierre et Marie Curie, Hopital Broussais, Paris, France; and
Institute of Cell Biology, National Research Council, Rome, Italy
Therapeutic preparations of normal human IgG for i.v. use (IVIg) exhibit a broad spectrum of immunoregulatory activities in vitro and in vivo. 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 of lymphocyte and monocyte lineage and in CD40-activated normal tonsillar B cells, involving, at least in part, Fas (CD95/APO-1) and activation of caspases. IVIg-induced apoptosis was higher in Fas-sensitive HuT78 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-transferase 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 proteases of the caspase family, caspase 1 (IL-1ß-converting enzyme) and caspase 3 (Yama/CPP32b), partially inhibited IVIg-induced apoptosis of CEM cells. Furthermore, cleavage of poly(A)DP-ribose polymerase into an 85-kDa signature death fragment was observed in CEM cells following IVIg treatment. Thus, normal IgG induces apoptosis in lymphocytes and 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 proliferation.
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