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Humoral immunity is increasingly recognized as an important factor in the rejection of organ transplants. In general, humoral rejection is treated with standard immunosuppressive drugs. The direct effect of these immunosuppressive drugs on B cells is not well known.Purified human B cells devoid of T cells were stimulated with CD40L expressing L cells, or by anti-CD40 mAb with or without Toll-like receptor triggering, all in the presence of B-cell activating cytokines. These three protocols resulted in various degrees of B-cell stimulation. We added four commonly used immunosuppressive drugs (tacrolimus, cyclosporin, mycophenolic acid [MPA], and rapamycin) to these cultures and tested a variety of parameters of B-cell activity including proliferation, apoptosis induction, and both IgM and IgG production.Tacrolimus and cyclosporin marginally inhibited B-cell proliferation and immunoglobulin production, and the extent of inhibition depended on the degree of the B-cell stimulation. In contrast, MPA and rapamycin profoundly inhibited both B-cell proliferation and immunoglobulin production, which was independent of the degree of B-cell stimulation. Both drugs induced B-cell apoptosis. Moreover, rapamycin caused a reduction in the number of B cells capable of producing immunoglobulins.Our data show that MPA and rapamycin are capable of strongly inhibiting B cells responses. This provides a rationale for the use of both MPA and rapamycin to prevent or counteract humoral responses.