Leflunomide-mediated suppression of antiviral antibody and T cell responses: Differential restoration by uridine

Background. Leflunomide is an isoxazol derivative with immunosuppressive ca pacities in various experimental allo- and xenotransplantation models. Two main mechanisms of action have been described: Inhibition of pyrimidine de novo synthesis and impairment of tyrosine phosphorylation. of different tyr osine kinases involved in receptor signaling via B cell and cytokine recept ors. Materials and Methods. Interference of Leflunomide with the IgM antibody re sponses to vesicular stomatitis virus (VSV, T-independent type 1), IgM to r ecombinant VSV glycoprotein (T-independent type 2), and IgG to lymphocytic choriomeningitis virus (LCMV, T-dependent) were analyzed whereas the cytoto xic T cell (CTL) response was examined after LCMV infection. Interference w ith the CD8(+) T cell-mediated autoimmune diabetes in a transgenic mouse ex pressing the LCMV-glycoprotein in the pancreatic islets was studied as a mo del for T cell-mediated autoimmune diseases. Uridine substitution experimen ts were performed to differentiate between the above mentioned two mechanis ms of action on different functions of the immune system in vivo. Results. Leflunomide at 35 mg/kg/day suppressed the humoral immune response against all antigens tested. Similar effects on T-independent compared to T-dependent antibody responses required two to four times higher drug doses . CTL responses to LCMV were considerably impaired. Uridine substitution pr evented lethal VSV encephalitis under Leflunomide treatment by restoring th e neutralizing IgM and IgG responses. However, the inhibition of LCMV speci fic CTLs and suppression of CD8(+) T cell-mediated autoimmune diabetes rema ined unaffected by additional uridine treatment. Conclusions. Leflunomide-mediated suppression of B cell and T helper cell a ctivity but not of CTLs largely depends on inhibition of pyrimidine de novo synthesis.