Tolerogenic dendritic cells and negative vaccination in transplantation: from rodents to clinical trials

Aurélie Moreau,Laurence Bouchet-Delbos,Gaëlle Bériou,Emilie Varey,Mercedes Segovia,Marcelo Hill,Maria-Cristina Cuturi

doi:10.3389/fimmu.2012.00218

Abstract

The use of immunosuppressive (IS) drugs to treat transplant recipients has markedly reduced the incidence of acute rejection and early graft loss. However, such treatments have numerous adverse side effects and fail to prevent chronic allograft dysfunction. In this context, therapies based on the adoptive transfer of regulatory cells are promising strategies to induce indefinite transplant survival. The use of tolerogenic dendritic cells (DC) has shown great potential, as preliminary experiments in rodents have demonstrated that administration of tolerogenic DC prolongs graft survival. Recipient DC, Donor DC, or Donor Ag-pulsed recipient DC have been used in preclinical studies and administration of these cells with suboptimal immunosuppression increases their tolerogenic potential. We have demonstrated that autologous unpulsed tolerogenic DC injected in the presence of suboptimal immunosuppression are able to induce Ag-specific allograft tolerance. We derived similar tolerogenic DC in different animal models (mice and non-human primates) and confirmed their protective abilities in vitro and in vivo. The mechanisms involved in the tolerance induced by autologous tolerogenic DC were also investigated. With the aim of using autologous DC in kidney transplant patients, we have developed and characterized tolerogenic monocyte-derived DC in humans. In this review, we will discuss the preclinical studies and describe our recent results from the generation and characterization of tolerogenic monocyte-derived DC in humans for a clinical application. We will also discuss the limits and difficulties in translating preclinical experiments to theclinic.

Highlights

The success rates of transplant surgery have significantly improved over the past fifty years
Donor dendritic cells (DC) mediate their suppressive effects on T cells through endogenous conventional DC from the recipient mouse (Wang et al, 2012). These results indicate that injected donor tolerogenic DC (TolDC) act as “donor Ag transporting cells”, which could be related to the DST protocol
Some studies have shown the ability of Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF)-derived DC to induce expansion of natural CD4+CD25+FoxP3+ Treg (Yamazaki et al, 2003; Emmer et al, 2006) whereas others have shown the ability of TolDC to generate Treg from naive CD4+CD25− T cells (Fujita et al, 2007)

Summary

Introduction

The success rates of transplant surgery have significantly improved over the past fifty years. Recipient DC the day before the transplant induces longer graft survival than the injection of donor DC (Peche et al, 2005). The third-party skin graft was rejected, showing that the tolerance induced by recipient TolDC + LF 15-0195 was donor specific (Beriou et al, 2005).

Results

Conclusion