부산대학교 도서관

Leflunomide, a potent disease‐modifying antirheumatic drug of the isoxazole class, exhibits antiinflammatory, antiproliferative, and immunosuppressive effects by largely unknown mechanisms, although alterations of pyrimidine synthesis have been proposed. Successful immune responsiveness requires T cell activation by interaction with antigen‐presenting cells (APCs), and integrin activation and formation of an immunologic synapse (IS). In this study, we evaluated the impact of the active leflunomide metabolite teriflunomide on T cell integrin activation, evolution of the IS, and antigen‐specific formation of stable T cell/APC conjugates.Effects of pharmacologic concentrations of teriflunomide on CD3/CD28‐ and lymphocyte function–associated antigen 1–induced signal transduction and activation of primary human T cells were investigated. Furthermore, T cells were stimulated with superantigen‐ and antigen‐pulsed APCs to study relocalization of molecules to the IS and T cell/APC conjugate formation.Teriflunomide inhibited T cell receptor (TCR)/CD3–mediated calcium mobilization, but other critical T cell signaling events, including activation of MAPK and NF‐κB, remained unaltered. In contrast, inhibition of TCR/CD3‐triggered β1,2 integrin avidity and integrin‐mediated costimulation (outside‐in signaling) by teriflunomide revealed a striking interference with integrin function that was independent of altered pyrimidine synthesis. Moreover, teriflunomide abolished molecule relocalization to the IS and induction of T cell/APC conjugates.These data show that the active metabolite of leflunomide prevents the interaction of T cells with APCs to form an IS. Since IS formation is crucial for eliciting an immune response, this novel mechanism could underlie the beneficial effects of leflunomide in immune‐mediated disorders such as rheumatoid arthritis. [ABSTRACT FROM AUTHOR]