BREQUINAR SODIUM INHIBITS INTERLEUKIN-6-INDUCED DIFFERENTIATION OF A HUMAN B-CELL LINE INTO IGM-SECRETING PLASMA-CELLS

Brequinar sodium (BQR) has been shown recently to be a potent immunosu ppressive agent. This property has been attributed to the capacity of BQR to inhibit de novo pyrimidine nucleoside biosynthesis and conseque ntly, to blockade the synthesis both of DNA and RNA. The influence of this new immunosuppressant on lymphocyte function has not been fully c haracterized. To determine the potential efficacy of BQR for the contr ol of antibody-mediated graft rejection, which is of particular signif icance in the context of xenotransplantation, we have examined the inf luence of the drug on interleukin-6-dependent IgM production by the hu man B-cell line, SKW 6.4. At concentrations up to 10 mug/ml, BQR did n ot affect concanavalin A (Con A)-induced human peripheral blood lympho cyte proliferation or IL-6 production by blood mononuclear leucocytes. In contrast, the drug was very effective in inhibiting IL-6-stimulate d IgM production by SKW 6.4 cells, with an optimal inhibitory concentr ation of 0.3 mug/ml. As expected, addition of exogenous uridine (0.1 m M), the precursor of uridine triphosphate (UTP), reversed the inhibito ry effect of BQR on antibody production, while cytidine (0.1 mM) poten tiated the inhibitory activity of the drug. It was further demonstrate d that the inhibition of IgM production was unrelated to DNA synthesis , indicating that BQR may affect IL-6 signal transduction and IgM prod uction in SKW 6.4 cells independent of any effect on cell proliferatio n.