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Induction of Fas (Apo-1, CD95)-Mediated Apoptosis of Activated
Lymphocytes by Polyclonal Antithymocyte Globulins
Laurent Genestier,
Sylvie Fournel,
Monique Flacher,
Olga Assossou,
Jean-Pierre Revillard, and
Nathalie Bonnefoy-Berard
From the Laboratory of Immunology, INSERM, Hôpital E. Herriot,
Lyon, France.
Polyclonal horse antilymphocyte and rabbit antithymocyte globulins
(ATGs) are currently used in severe aplastic anemia and for the
treatment of organ allograft acute rejection and graft-versus-host disease. ATG treatment induces a major depletion of peripheral blood
lymphocytes, which contributes to its overall immunosuppressive effects. Several mechanisms that may account for lymphocyte lysis were
investigated in vitro. At high concentrations (.1 to 1 mg/mL) ATGs
activate the human classic complement pathway and induce lysis of both
resting and phytohemagglutinin (PHA)-activated peripheral blood
mononuclear cells. At low, submitogenic, concentration ATGs induce
antibody-dependent cell cytotoxicity of PHA-activated cells, but not
resting cells. They also trigger surface Fas (Apo-1, CD95) expression
in naive T cells and Fas-ligand gene and protein expression in both
naive and primed T cells, resulting in Fas/Fas-L interaction-mediated cell death. ATG-induced apoptosis and Fas-L expression were not observed with an ATG preparation lacking CD2 and CD3 antibodies. Susceptibility to ATG-induced apoptosis was restricted to activated cells, dependent on IL-2, and prevented by Cyclosporin A, FK506, and
rapamycin. The data suggest that low doses of ATGs could
be clinically evaluated in treatments aiming at the selective deletion of in vivo activated T cells in order to avoid massive lymphocyte depletion and subsequent immunodeficiency.
Blood, Vol. 91 No. 7 (April 1), 1998:
pp. 2360-2368
© 1998 by The American Society of Hematology.
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