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 for i.v. use (i.v.Ig) exhibit a broad spectrum of immunoregulatory activities in vitro and in vivo. I.v.Ig 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 i.v.Ig 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. I.v.Ig-induced apoptosis was higher in Fas-sensitive HuT78 cells than in Fas-resistant HuT78.B1 mutant cells, and soluble Fas inhibited IVIg-induced apoptosis. I.v.Ig immunoprecipitated Fas from Fas-expressing transfectants and recognized purified Fas/glutathione-S-transferase fusion proteins upon immunoblotting. Affinity-purified anti-Fas Abs from i.v.Ig induced apoptosis of CEM T cells at a 120-fold lower concentration than unfractionated i.v.Ig. Inhibitors of cysteine proteases of the caspase family, caspase 1 (IL-1beta-converting enzyme) and caspase 3 (Yama/CPP32b), partially inhibited i.v.Ig-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 i.v.Ig 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 i.v.Ig in autoimmune diseases, and suggest a role of normal Ig in controlling cell death and proliferation.
Institut National de la Santé et de la Recherche Médicale U430, Université Pierre et Marie Curie, Paris, France.
N K
NK
Prasad
G
G
Papoff
A
A
Zeuner
E
E
Bonnin
M D
MD
Kazatchkine
G
G
Ruberti
S V
SV
Kaveri
D000818:Animals; D000918:Antibody Specificity; D017209:Apoptosis / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D019013:CD40 Antigens / Q000502:physiology; D016923:Cell Death / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D007106:Immune Sera / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification; D016756:Immunoglobulins, Intravenous / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008213:Lymphocyte Activation; D051379:Mice; D019463:Mice, Inbred MRL lpr; D009000:Monocytes / Q000166:cytology* / Q000276:immunology; D014066:Palatine Tonsil / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000276:immunology; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000235:genetics / Q000276:immunology / Q000502:physiology*
D019013:CD40 Antigens; D007106:Immune Sera; D016756:Immunoglobulins, Intravenous; D019014:fas Receptor; D003546:Cysteine Endopeptidases