Pharmacologic, biologic, and genetic engineering approaches to potentiation of donor-derived dendritic cell tolerogenicity

Abstract

There are various approaches to the enhancement of dendritic cell (DC) tolerogenicity for the promotion of cell or organ allograft survival. Both pharmacologic and biologic agents, including several commonly used immunosuppressive drugs, and specific anti-inflammatory cytokines inhibit DC maturation, whereas co-stimulation-blocking agents can also promote the induction of antigen-specific T-cell unresponsiveness by DC. Delivery of genes encoding molecules that subvert T-cell responses by various mechanisms, and targeting of DC migration by selective manipulation of chemokine and chemokine receptor expression, represent additional promising strategies. In this short review, the authors consider those approaches that have been used to promote the tolerogenicity of donor-derived DC in experimental models. Whereas most work to date has focused on myeloid DC, manipulation of other DC subsets may also offer potential for improving the outcome of transplantation and enhancing tolerance induction. Early reports that immature myeloid dendritic cells (DC) could induce alloantigen-specific T-cell hyporesponsiveness in vitro were followed by demonstrations of the capacity of immature, donor-derived DC to promote organ transplant survival in major histocompatibility complex (MHC)-mismatched recipients. More recent evidence indicates that this property is shared by other DC subsets. Combination of donor-derived DC with co-stimulation blockade (anti-CD40 ligand [CD154] monoclonal antibody [mAb] administration) is a particularly effective means of enhancing the tolerogenicity of these donor cells and may be linked to the enhanced apoptotic death of alloreactive T cells. Other approaches to potentiating the tolerogenic activity and subverting the immunostimulatory role of donor DC including manipulation of their classic in vivo migratory activity are currently being explored with a view to clinical application of the most promising strategy.