Western and Chinese antirheumatic drug-induced T cell apoptotic DNA damageuses different caspase cascades and is independent of Fas/Fas ligand interaction

Spontaneous or therapeutic induction of T cell apoptosis plays a critical r ole in establishing transplantation tolerance and maintaining remission of autoimmune diseases. We investigated the mechanisms of apoptosis induced by Chinese and Western anti-rheumatic drugs (ARDs) in human T cells. We found that hydroxychloroquine, Tripterygium wilfordii hook F, and tetrandrine Je t), but not methotrexate, at therapeutic concentrations can cause T cell de ath. In addition, Tet selectively killed T cells, especially activated T ce lls. Although ARD-induced cytotoxicity was mediated through apoptotic mecha nisms, Fas/Fas ligand interaction was not required. We further demonstrated that the processes of phosphatidylserine externalization and DNA damage al ong the ARD-induced T cell apoptotic pathway could operate independently, a nd that selective inhibition of DNA damage by caspase inhibitors did not pr event T cells from undergoing cell death. Moreover, we found that Tet- and Tripterygium wilfordii hook F-induced T cell DNA damage required caspase-3 activity, and hydroxychloroquine-induced T cell DNA damage was mediated thr ough a caspase-3- and caspase-8-independent, but Z-Asp-Glu-Val-Asp-fluometh yl ketone-sensitive, signaling pathway. Finally, the observation that ARD-i nduced activation of caspase-3 in both Fas-sensitive and Fas-resistant Jurk at T cells indicates that Fas/Fas ligand interaction plays no role in ARD-i nduced T cell apoptosis. Our observations provide new information about the complex apoptotic mechanisms of ARDs, and have implications for combining Western and Chinese ARDs that have different immunomodulatory mechanisms in the therapy of autoimmune diseases and transplantation rejection.