How self-tolerance and the immunosuppressive drug FK506 prevent B-cell mitogenesis

Therapy for transplant rejection, autoimmune disease and allergy must targe t mature lymphocytes that have escaped censoring during their development. FK506 and cyclosporin are immunosuppressants which block three antigen-rece ptor signalling pathways (NFAT, NF kappa B and JNK), through inhibition of calcineurin(1), and inhibit mature lymphocyte proliferation to antigen(2-4) Neither drug induces long-lived tolerance in vivo, however, necessitating chronic use with adverse side effects. Physiological mechanisms of peripher al tolerance to self-antigens provide an opportunity to emulate these proce sses pharmacologically. Here we use gene-expression arrays to provide a mol ecular explanation for the loss of mitogenic response in peripheral B-cell anergy, one aspect of immunological tolerance(5). Self-antigen induces a se t of genes that includes negative regulators of signalling and transcriptio n but not genes that promote proliferation. FK506 interferes with calcium-d ependent components of the tolerance response and blocks an unexpectedly sm all fraction of the activation response. Many genes that were not previousl y connected to self-tolerance are revealed, and our findings provide a mole cular fingerprint for the development of improved immunosuppressants that p revent lymphocyte activation without blocking peripheral tolerance.