Tolerogenic dendritic cells and their role in transplantation

Abstract

The pursuit of clinical transplant tolerance has led to enhanced understanding of mechanisms underlying immune regulation, including the characterization of immune regulatory cells, in particular antigen-presenting cells (APC) and regulatory T cells (Treg), that may play key roles in promoting operational tolerance. Dendritic cells (DC) are highly efficient APC that have been studied extensively in rodents and humans, and more recently in non-human primates. Owing to their ability to regulate both innate and adaptive immune responses, DC are considered to play crucial roles in directing the alloimmune response towards transplant tolerance or rejection. Mechanisms via which they can promote central and peripheral tolerance include clonal deletion, the induction of Treg, and inhibition of memory T cell responses. These properties have led to the use of tolerogenic DC as a therapeutic strategy to promote organ transplant tolerance. In rodents, infusion of donor- or recipient-derived tolerogenic DC can extensively prolong donor-specific allograft survival, in association with regulation of the host T cell response. In clinical transplantation, progress has been made in monitoring DC in relation to graft outcome, including studies in operational liver transplant tolerance. Although clinical trials involving immunotherapeutic DC for patients with cancer are ongoing, implementation of human DC therapy in clinical transplantation will require assessment of various critical issues. These include cell isolation and purification techniques, source, route and timing of administration, and combination immunosuppressive therapy. With ongoing non-human primate studies focused on DC therapy, these logistics can be investigated seeking the optimal approaches. The scientific rationale for implementation of tolerogenic DC therapy to promote clinical transplant tolerance is strong. Evaluation of technical and therapeutic logistic issues is an important next step prior to the application of tolerogenic DC in clinical organ transplantation.

Figure 1

Developmental stages of therapeutic tol DC in allotransplantation Properties and phenotype of human and murine tol DC have been characterized in vitro and their potential to promote tolerance to organ allografts in vivo has been confirmed in rodents. Pre-clinical studies in a clinically relevant model (non-human primate) are required to evaluate tol DC as a therapeutic regimen and to validate its safety and efficacy. Clinical trials in humans will require assessment of various critical issues in relation to DC therapy and the outcome of organ allotransplantation.

Figure 2

Therapeutic tol-DC in organ allotransplantation Tol DC can be either recipient- or donor-derived (in the case of living-donor transplantation). Recipient DC can be pulsed with donor antigen in various forms (donor cell lysate, exosomes, apoptotic bodies). During tol DC preparation, DC can be treated pharmacologically e.g. with dexamethasone VitD3/IL-10 to induce maturation resistance. Typical tol DC secrete and express cell surface regulatory molecules, that mediate the tolerogenic influence of tol DC on recipient T cells. As a result, tolerance to the donor antigen can be achieved through induction of regulatory T cells, as well as via the induction of anergy and deletion of effector and memory T cells. Additionally, infused tol DC can be reprocessed by recipient antigen-presenting cells (APC), promoting organ allograft survival through the indirect pathway. IDO, indoleamine dioxygenase; PD-L1, programed death ligand-1; HO-1, hemoxygenase-1.

Figure 3

Logistics of tol-DC therapy in organ allotransplantation Evaluation of logistic issues will be needed for implementation of therapeutic tol DC. Prior to DC infusion, these include the source, recovery and purity of the DC, and preparation and pharmacologic treatment of tol DC. On tol DC infusion, additional logistics will be assessed. These include time and route of administration, and the frequency and dose of tol DC administered. Additionally, concomitant use of various immunosuppressive agents may have variable effects on DC viability, migration and function as is evident from studies of DC in human transplant patients (Table 1).