title: Calcineurin inhibitors affect B cell antibody responses indirectly by interfering with T cell help.
abstract: In general, humoral immune responses depend critically upon T cell help. In transplantation, prevention or treatment of humoral rejection therefore require drugs that ideally inhibit both B cell and T helper cell activity. Here, we studied the effects of commonly used immunosuppressive drugs [tacrolimus, cyclosporin, mycophenolic acid (MPA) and rapamycin] on T cell helper activity and on T cell-dependent B cell responses. T cells were activated polyclonally in the presence of immunosuppressive drugs in order to analyse the effect of these drugs on T cell proliferation, co-stimulatory ligand expression and cytokines. The impact of immunosuppressive drugs on T cell-dependent immunoglobulin production by B cells was addressed in T-B cell co-cultures. All drugs affected T cell proliferation and attenuated T cell co-stimulatory ligand (CD154 and CD278) expression when T cells were activated polyclonally. Tacrolimus, cyclosporin and rapamycin also attenuated B cell stimulatory cytokine mRNA levels in T cells. As a consequence, a decrease in immunoglobulin levels was observed in autologous T-B cell co-cultures, where T cell help is essential for immunoglobulin production. In contrast, when pre-activated T cells were used to stimulate autologous B cells, calcineurin inhibitors failed to inhibit B cell immunoglobulin production, whereas MPA and rapamycin did show inhibition. From these studies, it is evident that calcineurin inhibitors affect the humoral immune response by interfering with T helper signals, but not by targeting B cells directly. Furthermore, our studies support the necessity of intervening in T cell helper function to attenuate humoral responses.
authors.affiliation: Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Heidt
authors.forename: D L
authors.initials: DL
authors.lastname: Roelen
authors.forename: C
authors.initials: C
authors.lastname: Eijsink
authors.forename: M
authors.initials: M
authors.lastname: Eikmans
authors.forename: C
authors.initials: C
authors.lastname: van Kooten
authors.forename: F H J
authors.initials: FH
authors.lastname: Claas
authors.forename: A
authors.initials: A
authors.lastname: Mulder
mesh_terms: D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D065095:Calcineurin Inhibitors; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D009173:Mycophenolic Acid / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D020123:Sirolimus / Q000494:pharmacology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D065095:Calcineurin Inhibitors; D016207:Cytokines; D007136:Immunoglobulins; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus