Pathways for self-tolerance and the treatment of autoimmune diseases

Antigen delivers both immunogenic and tolerogenic signals to lymphocytes. T he outcome of antigen exposure represents a complex integration of the timi ng of antigen binding with signals from many other immunogenic and toleroge nic costimulatory pathways. A road map of these signalling pathways is only beginning to be charted, revealing the mechansim of action and limitations of current immunotherapeutic agents and the points of attack for new agent s. Ciclosporin and tacrolimus interfere with tolerogenic signals from antig en in addition to blocking immunogenic signals, thus preventing active esta blishment of tolerance. Corticosteroids inhibit a key immunogenic pathway, NF kappaB, and more specific inhibitors of this pathway may allow tolerance to be actively established while immune responses are blocked. New experim ental therapies aim to mimic tolerogenic antigen signals by chronically sti mulating antigen receptors with antigen or antibodies to the receptor, or a im to block costimulatory pathways involving CD40 ligand, B7, or interleuki n 2. Obtaining the desired response with these strategies is unpredictable because many of these signals have both tolerogenic and immunogenic roles. The cause of autoimmune diseases has been determined for several rare monog enic disorders, revealing inherited deficiencies in tolerogenic costimulato ry pathways such as FAS. Common autoimmune disorders may have a biochemical ly related pathogenesis.