Pyrimethamine (2,4-Diamino-5-p-chlorophenyl-6-ethyl-pyrimidine) Induces Apoptosis of Freshly Isolated Human T Lymphocytes,Bypassing CD95/Fas Molecule but Involving Its Intrinsic Pathway

摘要

Pyrimethamine (2,4-diamino-5-p-chlorophenyl-6-ethyl-pyrimi-dine),a folic acid antagonist,may exert,in addition to antipro-tozoan effects,immunomodulating activities,including induction of peripheral blood lymphocyte apoptosis.However,the molecular mechanisms underlying this proapoptotic activity remain to be elucidated.Here we show that pyrimethamine,used at a pharmacologically relevant concentration,induced per se apoptosis of activated lymphocytes via the activation of the caspase-8- and caspase-10-dependent cascade and subsequent mitochondrial depolarization.Importantly,this seems to occur independently from CD95/Fas engagement.The proapoptotic activity of pyrimethamine was further confirmed in a patient with autoimmune lymphoproliferative syndrome,an immune disorder associated with a defect of Fas-induced apoptosis.In this patient,pyrimethamine treatment resulted in a "normalization" of lymphocyte apoptosis with a significant amelioration of laboratory parameters.Altogether,these results suggest a mechanism for pyrimethamine-mediated apoptosis that seems to bypass CD95/Fas engagement but fully overlaps CD95/Fas-induced subcellular pathway.On these bases,a reappraisal of the use of pyrimethamine in immune lymphoproliferative disorders characterized by defects in CD95/Fas-me-diated apoptosis should be taken into account.