Dendritic cells and immunoregulation in transplantation and immunopathology
Aurélie Moreau
Research Scientist

Cell-based immunotherapy with tolerogenic dendritic cells is recognized as an efficient means of promoting antigen specific tolerance since several years. Based on our expertise in rodents, we recently established a GMP-compliant manufacturing process to derive human Autologous Tolerogenic DCs (ATDCs). Following the characterization of these cells, the safety of ATDC immunotherapy is currently evaluated in a Phase I/II clinical trial in kidney transplant patients. In order to perform a Phase IIb clinical trial in kidney transplantation using these cells and then enlarge their application to the treatments of autoimmune and inflammatory diseases, we are currently working on molecular mechanisms of action of these cells.   

Description

Kidney transplantation is the only curative treatment for patients suffering from end-stage renal disease. However, without treatment, the development of an immune response against the donor organ by the transplant patients leads to graft destruction. Immunosuppressive drugs are used to decrease the incidence of acute rejection and considerably improved the short-term prospects of renal transplant recipients. Unfortunately, the use of these drugs is associated to drug toxicities, increased risks of infections and the occurrence of certain types of cancers. A primary objective in transplantation medicine today is to find new therapeutic tools. Cell therapy appears as an innovative and promising strategy to address this challenge. The strength of cell therapy is that this therapy will induce an antigen-specific tolerance and not a general immunosuppression of the patients. Several candidates such as regulatory T cells (Tregs, Tr1 cells), regulatory macrophages or tolerogenic dendritic cells (DCs) have been gaining interest as an efficient means of promoting antigen specific tolerance over recent years.

Previous works from the team reported the potential of tolerogenic rodent DCs to impressively prolong cardiac, skin and islet allograft survivals (1-6). In these three models, animals received non-pulsed autologous tolerogenic DCs. Studies performed by our group and others highlighted that injected tolerogenic DCs are able to migrate to lymphoid organs or grafts where they uptake allo-antigen. Furthermore, the potency of tolerogenic DCs therapy was linked to an increase of regulatory T cells in lymphoid tissues. In humans, protocols of tolerogenic DC generation have been described following exposition of blood monocytes to pharmacological agents, anti-inflammatory biologicals, or genetic modification. Strategies for the manufacturing of clinical-grade tolerogenic DCs are emerged only few years ago and clinical application is today seriously investigated. Based on our expertise of tolerogenic DCs in rodents and primates (1-9), we have driven forward the clinical application of tolerogenic DC in transplantation. Indeed, we recently established a GMP-compliant manufacturing process to derive human tolerogenic DCs named ATDCs (autologous tolerogenic DCs) and these human ATDCs are currently administered to living donor renal transplant recipients to evaluate the safety and efficacy of this cellular immunotherapy in solid organ transplantation in a phase I/II clinical trial (The ONE Study ATDC trial - NTC0225055) (Figure 1). This trial will make the proof of concept of the safe administration of ATDCs in humans.

We recently performed some microarray analysis on ATDCs and other in vitro-derived myeloid cell types and our results indicate that ATDCs constitute a highly separated subset of DCs. Furthermore, analysis of gene expression in these microarrays highlighted interested genes highly over-expressed in ATDCs compared to others populations of monocytes derived antigen-presenting cells. We are therefore currently working on the involvement of few molecules in ATDC mechanisms of action. In depth investigations of the role of these molecules will precise ATDC mechanisms of action and will allow us to perform a phase IIb clinical trial in kidney transplantation. These results could further lead to an expansion of ATDC clinical use to the treatment of patients with autoimmune or inflammatory diseases.

References

1. Peche H, Trinite B, Martinet B, Cuturi MC. Prolongation of heart allograft survival by immature dendritic cells generated from recipient type bone marrow progenitors. American journal of transplantation. Feb 2005;5(2):255-267.

2. Beriou G, Peche H, Guillonneau C, Merieau E, Cuturi MC. Donor-specific allograft tolerance by administration of recipient-derived immature dendritic cells and suboptimal immunosuppression. Transplantation. Apr 27 2005;79(8):969-972.

3. Hill M, Thebault P, Segovia M, et al. Cell therapy with autologous tolerogenic dendritic cells induces allograft tolerance through interferon-gamma and epstein-barr virus-induced gene 3. American journal of transplantation. Oct 2011;11(10):2036-2045.

4. Baas MC, Kuhn C, Valette F, et al. Combining autologous dendritic cell therapy with CD3 antibodies promotes regulatory T cells and permanent islet allograft acceptance. J Immunol. Nov 1 2014;193(9):4696-4703.

5. Segovia M, Louvet C, Charnet P, et al. Autologous dendritic cells prolong allograft survival through Tmem176b-dependent antigen cross-presentation. American journal of transplantation. May 2014;14(5):1021-1031.

6. Carretero-Iglesia L, Bouchet-Delbos L, Louvet C, et al. Comparative study of the immunoregulatory capacity of in vitro generated tolerogenic dendritic cells, suppressor macrophages and myeloid-derived suppressor cells Transplantation 2016 Oct;100(10):2079-2089

7. Moreau A, Chiffoleau E, Beriou G, et al. Superiority of bone marrow-derived dendritic cells over monocyte-derived ones for the expansion of regulatory T cells in the macaque. Transplantation. May 15 2008;85(9):1351-1356.

8. Moreau A, Hill M, Thebault P, et al. Tolerogenic dendritic cells actively inhibit T cells through heme oxygenase-1 in rodents and in nonhuman primates. FASEB J. Sep 2009;23(9):3070-3077.

9. Moreau A VC, Segovia M, Devaux M, Guilbaud M, Tilly G, Jaulin N, Le Duff J, Cherel Y, Deschamps JY, Anegon I, Moullier P, Cuturi MC, Adjali O. Generation and in vivo evaluation of IL-10-treated dendritic cells in a non-human primate model of AAV-based gene transfer. Mol Ther Methods Clin Dev. Jul 23 2014;1:14028.