Tolerogenic Dendritic Cells in Solid Organ Transplantation: Where Do We Stand?

Abstract

Over the past century, solid organ transplantation has been improved both at a surgical and postoperative level. However, despite the improvement in efficiency, safety, and survival, we are still far from obtaining full acceptance of all kinds of allograft in the absence of concomitant treatments. Today, transplanted patients are treated with immunosuppressive drugs (IS) to minimize immunological response in order to prevent graft rejection. Nevertheless, the lack of specificity of IS leads to an increase in the risk of cancer and infections. At this point, cell therapies have been shown as a novel promising resource to minimize the use of IS in transplantation. The main strength of cell therapy is the opportunity to generate allograft-specific tolerance, promoting in this way long-term allograft survival. Among several other regulatory cell types, tolerogenic monocyte-derived dendritic cells (Tol-MoDCs) appear to be an interesting candidate for cell therapy due to their ability to perform specific antigen presentation and to polarize immune response to immunotolerance. In this review, we describe the characteristics and the mechanisms of action of both human Tol-MoDCs and rodent tolerogenic bone marrow-derived DCs (Tol-BMDCs). Furthermore, studies performed in transplantation models in rodents and non-human primates corroborate the potential of Tol-BMDCs for immunoregulation. In consequence, Tol-MoDCs have been recently evaluated in sundry clinical trials in autoimmune diseases and shown to be safe. In addition to autoimmune diseases clinical trials, Tol-MoDC is currently used in the first phase I/II clinical trials in transplantation. Translation of Tol-MoDCs to clinical application in transplantation will also be discussed in this review.

Keywords: autologous tolerogenic dendritic cells; cell therapy; clinical trial; mechanisms; safety; transplantation.

Figure 1

Pro-inflammatory and tolerogenic dendritic cell profile. Pro-inflammatory dendritic cells (DCs) are characterized by a high expression of costimulatory molecules (CD80 and CD86) and pro-inflammatory cytokines and by an ability to stimulate T-cell proliferation. Tolerogenic DCs display a low expression of costimulatory molecules, which are resistant to maturation, and express immunomodulatory molecules. Tolerogenic DCs have also suppressive activity toward T cells and promote regulatory T cells. Both pro-inflammatory and tolerogenic DCs express CD11b, CD11c, and MHCI.

Figure 2

Tolerogenic dendritic cells (DC) mechanisms. Tolerogenic DCs display different mechanisms of action to impair T-cell proliferation and stimulate regulatory cell induction. These mechanisms can be differentiated in contact-dependent and contact-independent mechanisms. Contact-dependent mechanisms include Inducible T-cell costimulator-ligand, Fas, programmed death-ligand 1, and human leukocyte antigen-G. Contact-independent mechanisms include the expression of immunomodulatory cytokines and the production of small molecules, such as carbon monoxide and nitric oxide. TolDC can also act indirectly through L-Arg and L-Trp deprivation.

Figure 3

Regulatory cells induced by tolerogenic dendritic cells (DC). Tolerogenic DCs are able to induce different populations of regulatory T and B cells. Each population has different immunomodulatory mechanisms to prevent allogeneic proliferation. CD4⁺CD25⁺FoxP3^hi regulatory T (Treg) display contact-independent mechanisms, such as cytotoxic T-lymphocyte associated protein-4 and lymphocyte-activation gene 3 and contact-independent mechanisms by their secretion of IL-10, TGF-β, and IL-35. They are also able to produce adenosine by the degradation of ATP. Tr1 cells and CD8⁺Treg are known to produce IL-10. Breg express anti-inflammatory molecules, Granzyme B, and immunoglobulins.