SUMMARYIn order to assess the direet effects of eyclosporine A (CsA) and rapamycin on B cells, we utilized a two-segment eulture system of highly purified B lymphocytes consisting of induction (activation) in the presenee of the formalinized Staphylococcus aureus bacteria and IL-2. and diiTerentiation, respectively, in the presence of various combinations of cytokines. Results show that rapamycin strongly inhibited produetion of both IgM and IgG measured at the end of the secondary culture stjpported by IL-2/IL-6. whereas CsA up-regulated the immunoglobulin production. The stimulatory efVeet of CsA was also observed when preaetivated B cells were recultured in absence of any cytokines. These results show that rapamycin and CsA have dearly distinct effects on human B lymphocyte responses in vitro. Rapamyein is a more potent in vitro immunosuppressant of B lytnphocytes than CsA. It is effective at significantly lower concentrations, and it does not stimulate either the proliferation or antibody production by preactivated B cells.