Taming the lions: manipulating dendritic cells for use as negative cellular vaccines in organ transplantation

Abstract

Dendritic cells are well known for their potent ability, when fully differentiated or 'mature', to stimulate immune responses to antigens they present efficiently to T cells. Mature DC have been used as experimental cellular vaccines against cancer, an approach that has produced limited immune responses and tumor regressions in patients with late-stage disease. Contrastingly, with respect to therapy of organ transplant rejection, we highlight herein how immature/maturation-resistant dendritic cells are emerging as 'negative cellular vaccines', with the ability to induce anergy/apoptosis in alloreactive T cells, while potentially stimulating regulatory T-cell populations. New insights have shed increasing light on dendritic cell immunobiology and the complex processes by which dendritic cell subsets perform both stimulatory and tolerogenic functions. Alloantigen-pulsed host-derived dendritic cells, conditioned with immunosuppressive agents (e.g. rapamycin (RAPA) or dexamethasone) or anti-inflammatory cytokines (e.g. IL-10), are resistance to maturation, and when infused systemically, can promote experimental transplant tolerance, especially when combined with low-dose immunosuppression. Such 'negative' dendritic cell cellular vaccines are proving effective at stimulating/enriching for alloantigen-specific regulatory T cell. Increased understanding of what makes dendritic cells tolerogenic, accompanied by the identification of agents that stably inhibit dendritic cell maturation in the face of proinflammatory stimuli, has given rise to several promising experimental tolerance-inducing protocols. Their translation into clinical testing has the potential to reduce patients' reliance on indefinite, drug-based immunosuppression.