INHIBITION OF HUMAN B-LYMPHOCYTE CELL-CYCLE PROGRESSION AND DIFFERENTIATION BY RAPAMYCIN

In this study, we have analyzed the effects of the immunosuppressive a gent rapamycin on the activation of highly purified normal human B lym phocytes. When the polyclonal activators Staphylococcus aureus (SA) an d soluble CD40 ligand (CD40L) were used to stimulate B cells, rapamyci n inhibited both interleukin 2 (IL2)-dependent and -independent prolif eration, as well as IL2-dependent differentiation into antibody-secret ing cells. Cell cycle analysis indicated that rapamycin inhibited the progression of SA+IL2-stimulated B cells past the mid-G(1) phase of th e cell cycle. To begin to identify rapamycin-sensitive signaling event s essential for B cell activation, we examined the effects of rapamyci n on p34(cdc2) and p33(cdk2) kinase activities. SA+IL2 stimulation ind uced the activation of both cyclin-dependent kinases. Of interest, rap amycin abrogated the activation of both p34(cdc2) and p33(cdk2). Our r esults indicate therefore that rapamycin inhibits a number of SA- and CD40L-inducible events that may be necessary for both entry into S pha se and for permitting subsequent B cell differentiation. These studies emphasize the utility of this drug as a tool to begin to dissect the activation pathways utilized by human B eels, as well as to provide im plications for the therapeutic use of rapamycin in vivo. (C) 1994 Acad emic Press, Inc.