Altering immune tolerance therapeutically: the power of negative thinking

The etiology of most human autoimmune diseases remains largely unknown. However, investigators have identified several negative regulatory mechanisms acting at the level of innate and/or adaptive immunity. Mutations resulting in a deficiency of some key regulatory molecules are associated with systemic or organ-specific inflammatory disorders, which often have a prominent autoimmune component. Genetic studies have implicated the negative regulator cytotoxic T-lymphocyte antigen 4 (CTLA-4) and other regulatory molecules in human autoimmune diseases. In addition to CTLA-4, key inhibitory molecules include programmed death 1 and B and T lymphocyte attenuator. Transforming growth factor beta1 and interleukin-10 also play major anti-inflammatory and regulatory roles. Tumor cells and infectious agents use negative regulatory pathways to escape immunity. The therapeutic blockage of negative signaling (particularly of CTLA-4) increases immunity against tumor antigens but also induces or aggravates autoimmune diseases. It appears that under normal conditions, the immune system is under strong "negative influences" that prevent autoimmunity and that release of this suppression results in disease. Regulation involves communication between the immune system and nonlymphoid tissues, and the latter can deliver inhibitory or stimulatory signals. Recent studies reveal that the generation of negative signals by selective engagement of inhibitory molecules is feasible and is likely to be of therapeutic benefit in autoimmune diseases and allograft rejection.