Immunotherapy Targeting the CD40/CD154 Costimulatory Pathway for Treatment of Autoimmune Disease

The CD154–CD40 ligand pair interaction plays a central role in both induction of the immune response and in immune effector functions. Indeed, many animal disease models and human autoimmune diseases have demonstrated a central role for CD154 expression. The expression of CD154 is very tightly regulated by the immune system through a number of non-redundant overlapping mechanisms that ensure its limited initial induction, along with its temporal maintenance and rapid elimination from the cell surface, and its functional neutralization by the release of soluble CD40. In this review, we discuss the current state of understanding of CD154 regulation during the activation of the immune system and describe numerous strategic mechanisms by which modulation of CD154–CD40 interactions may be applied to treat autoimmune disease.