| Summary: | Development of the acquired immune response is dependent on the signaling of CD40 by its ligand, CD154. These molecules govern both the magnitude and quality of humoral- and cell-mediated immunity. A litany of studies have conclusively documented that blockade of this ligand-receptor pair can prevent, and also intervene in the progression of antibody- and cell-mediated autoimmune diseases, and can instill long-lived allogeneic and xenogeneic graft tolerance. Many effector mechanisms of inflammation are abolished as a result of CD154 blockade, but we are now beginning to understand that CD154 blockade, may, in some instances engender long-lived, antigen-specific tolerance. In the context of transplantation tolerance, we present as an hypothesis that αCD154 blockade is most effective at inducing long-lived allospecific tolerance if anergy and regulation (by the induction of regulatory T cell activities) can be elicited prior to the onslaught of inflammation that is induced by grafting ("pre-emptive" tolerance). This facet of anti-CD154 induced tolerance appears to co-opt the normal processes of peripheral tolerance induced by immature dendritic cells and can be exploited to induce long-lived antigen-specific tolerance. The underlying science and the prospects for inducing long-lived antigen-specific tolerance in a model of allograft tolerance through CD154 blockade are presented and discussed in this work
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