Cyclosporine a directly affects human and mouse b cell migration in vitro by disrupting a hIF-1 αdependent o2 sensing molecular switch

摘要

Calcineurin inhibitors (CNI), such as cyclosporine A (CyA), are used to reduce the risk of allograft rejection in solid organ transplant recipients, and prevent graft-versus-host disease in bone marrow transplantation [ ]. One side effect of CNI therapy is reduced antigen-specific B cell responsiveness, including hypogammaglobulinemia and reduced protective IgG responses to influenza and other vaccinations [ , ]. This effect has previously been thought to be primarily due to CD4 T cell inhibition [ ]. CNI directly inhibit CD4 T cell calcineurin signaling by preventing calcineurin dependent dephosphorylation of the transcription factor NFAT, blocking nuclear translocation, inhibiting IL-2 production and proliferation [ ]. In transplant recipients, CNI are thus thought to primarily suppress CD4 T cell help, indirectly causing B cell hypo-responsiveness and depressing antibody production [ ]. In contrast, direct effects of CNI on B cell function, in particular cellular migration, are sparsely described in the literature [ ].