INDUCTION OF FAS (APO-1, CD95)-MEDIATED APOPTOSIS OF ACTIVATED LYMPHOCYTES BY POLYCLONAL ANTITHYMOCYTE GLOBULINS

Polyclonal horse antilymphocyte and rabbit antithymocyte globulins (AT Gs) 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 me chanisms that may account for lymphocyte lysis were investigated in vi tro, At high concentrations (.1 to 1 mg/mL) ATGs activate the human cl assic complement pathway and induce lysis of both resting and phytohem agglutinin (PHA)-activated peripheral blood mononuclear cells. At low, submitogenic, concentration ATGs induce antibody-dependent cell cytot oxicity of PHA-activated cells, but not resting cells. They also trigg er surface Fas (Apo-1, CD95) expression in naive T cells and Fas-ligan d gene and protein expression in both naive and primed T cells, result ing in Fas/Fas-L interaction-mediated cell death. ATG-induced apoptosi s and Fas-L expression were not observed with an ATG preparation lacki ng CD2 and CD3 antibodies. Susceptibility to ATG-induced apoptosis was restricted to activated cells, dependent on IL-2, and prevented by Cy closporin A, FK506, and rapamycin. The data suggest that low doses of ATGs could be clinically evaluated in treatments aiming at the selecti ve deletion of in vivo activated T cells in order to avoid massive lym phocyte depletion and subsequent immunodeficiency. (C) 1998 by The Ame rican Society of Hematology.