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Polyclonal antithymocyte globulin (ATG) is widely used as an anti–T-cell agent for induction and treatment of acute cellular rejection in solid organ transplantation. The authors recently demonstrated that rabbit (r) ATG can be used in combination with plasmapheresis to effectively treat antibody-mediated renal allograft rejection. This observation suggested that rATG may have anti-B cell activity.The authors tested the complement-independent, apoptosis-inducing properties of rATG on CD27− naive B cells, CD40 ligand-activated B cells, and plasma cells in vitro by annexin V staining, subdiploid DNA content, caspase activation, and loss of mitochondrial membrane polarity. Potential surface targets for rATG were assayed by competitive inhibition of monoclonal antibody binding.Rabbit ATG strongly induced apoptosis in vitro against naive, activated B cells and bone marrow resident plasma cells at clinically relevant concentrations (1–100 ng/mL). The authors found rATG activity against numerous B-cell surface proteins and observed that crosslinking of CD30, CD38, CD95, CD80, and HLA-DR likely accounts for this activity. F(ab)2 fragments of rATG showed 90% of the activity of the intact molecule, suggesting participation of the Fc fragment. Inhibition of caspase- and cathepsin-dependent apoptotic pathways partially inhibits rATG-induced B-cell apoptosis. Immunohistochemical staining of pediatric thymi demonstrated the presence of CD20+ B cells and CD138+ plasma cells within the thymic parenchyma, which accounts for the anti–B-cell activity in rATG.Polyclonal rATG induces complement-independent apoptosis of naive, activated, and plasma B cells. This effect appears to involve the caspase- and cathepsin-mediated apoptosis pathways.