CYCLOSPORINE-A INHIBITS CD40 LIGAND EXPRESSION IN T-LYMPHOCYTES

The ligand for CD40 is expressed on activated T lymphocytes and delive rs contact-dependent activation signals to B lymphocytes. The mechanis ms 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. Cyclospo rin A analogues inhibited CD40 ligand expression with a potency mirror ing the ability of each compound to inhibit calcineurin activity, indi cating that calcineurin plays a key role in CD40 ligand gene expressio n. Cyclosporin A inhibited IL-4-driven CD40 ligand-dependent IgE isoty pe switching in PBMC but did not inhibit IgE synthesis induced by CD40 mAb plus IL-4. PBMC derived from transplant patients receiving cyclos porin 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.