title: Cyclosporin A inhibits CD40 ligand expression in T lymphocytes.
abstract: The ligand for CD40 is expressed on activated T lymphocytes and delivers contact-dependent activation signals to B lymphocytes. The mechanisms regulating CD40 ligand gene expression are largely unknown. Optimal expression of CD40 ligand required activation of protein kinase C and a rise in intracellular calcium concentration. CD40 ligand expression was inhibited by pretreatment of T cells with cyclosporin A. Cyclosporin A analogues inhibited CD40 ligand expression with a potency mirroring the ability of each compound to inhibit calcineurin activity, indicating that calcineurin plays a key role in CD40 ligand gene expression. Cyclosporin A inhibited IL-4-driven CD40 ligand-dependent IgE isotype switching in PBMC but did not inhibit IgE synthesis induced by CD40 mAb plus IL-4. PBMC derived from transplant patients receiving cyclosporin A failed to express CD40 ligand upon stimulation. These results suggest that patients receiving cyclosporin A may be deficient in CD40 ligand-dependent T cell help.
authors.affiliation: Division of Immunology, Children's Hospital, Boston, Massachusetts.
authors.forename: R
authors.initials: R
authors.lastname: Fuleihan
authors.forename: N
authors.initials: N
authors.lastname: Ramesh
authors.forename: A
authors.initials: A
authors.lastname: Horner
authors.forename: D
authors.initials: D
authors.lastname: Ahern
authors.forename: P J
authors.initials: PJ
authors.lastname: Belshaw
authors.forename: D G
authors.initials: DG
authors.lastname: Alberg
authors.forename: I
authors.initials: I
authors.lastname: Stamenkovic
authors.forename: W
authors.initials: W
authors.lastname: Harmon
authors.forename: R S
authors.initials: RS
authors.lastname: Geha
mesh_terms: D000293:Adolescent; D000328:Adult; D023201:CD40 Ligand; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000502:physiology; D002648:Child; D016572:Cyclosporine / Q000494:pharmacology*; D005260:Female; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000187:drug effects; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis*; D010749:Phosphoprotein Phosphatases / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000032:analysis; D013601:T-Lymphocytes / Q000737:chemistry / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D002148:Calmodulin-Binding Proteins; D008562:Membrane Glycoproteins; D015375:Receptors, Interleukin-2; D023201:CD40 Ligand; D016572:Cyclosporine; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D013755:Tetradecanoylphorbol Acetate