Cyclosporin A inhibits CD40 ligand expression in T lymphocytes.
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.
Fuleihan
R
R
Division of Immunology, Children's Hospital, Boston, Massachusetts.
Ramesh
N
N
Horner
A
A
Ahern
D
D
Belshaw
P J
PJ
Alberg
D G
DG
Stamenkovic
I
I
Harmon
W
W
Geha
R S
RS
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
D002148:Calmodulin-Binding Proteins; D008562:Membrane Glycoproteins; D015375:Receptors, Interleukin-2; D023201:CD40 Ligand; D016572:Cyclosporine; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D013755:Tetradecanoylphorbol Acetate