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

Abstract

Therapy for transplant rejection, autoimmune disease and allergy must target mature lymphocytes that have escaped censoring during their development. FK506 and cyclosporin are immunosuppressants which block three antigen-receptor signalling pathways (NFAT, NFκB and JNK), through inhibition of calcineurin, and inhibit mature lymphocyte proliferation to antigen. Neither drug induces long-lived tolerance in vivo, however, necessitating chronic use with adverse side effects. Physiological mechanisms of peripheral tolerance to self-antigens provide an opportunity to emulate these processes pharmacologically. Here we use gene-expression arrays to provide a molecular explanation for the loss of mitogenic response in peripheral B-cell anergy, one aspect of immunological tolerance. Self-antigen induces a set of genes that includes negative regulators of signalling and transcription but not genes that promote proliferation. FK506 interferes with calcium-dependent components of the tolerance response and blocks an unexpectedly small fraction of the activation response. Many genes that were not previously connected to self-tolerance are revealed, and our findings provide a molecular fingerprint for the development of improved immunosuppressants that prevent lymphocyte activation without blocking peripheral tolerance.