Pharmacological manipulation of dendritic cells in the pursuit of transplantation tolerance

Abstract

Although long-term immune suppression remains the intervention of choice for the treatment of allograft rejection, transplantation tolerance would achieve graft survival with fewer inherent risks. Although the use of dendritic cells for the induction of tolerance might confer antigen specificity, factors determining the balance between tolerogenicity and immunogenicity remain uncertain, as does the stability of the functional phenotype. Here, we review recent studies suggesting that pharmacological agents may profoundly influence this delicate balance and outline the insights they provide into parameters that contribute to the tolerogenic state. Recent findings have revealed that the inhibition of dendritic cell maturation by pharmacological intervention is not a prerequisite for the acquisition of tolerogenicity, but that susceptibility to a tolerogenic phenotype may vary between dendritic cell subsets and depend on the nature of maturation stimuli to which the cells are exposed. Furthermore, such studies have highlighted the degree to which the maintenance of tolerogenicity is influenced by local environmental factors, such as the cytokine milieu. Although the rational design of tolerogenic dendritic cells for modulating the outcome of organ transplantation remains ambitious, the use of pharmacological agents to influence their functional phenotype continues to illuminate the basic biology of this critical cell type.