Tolerogenic dendritic cells: promising cell therapy for acute kidney injury

There is still no established treatment for acute kidney injury (AKI), and the intervention of AKI remains limited to supportive treatments. Li et al. demonstrated the mechanism by which immune tolerance by dendritic cell ameliorates AKI in a mouse ischemia-reperfusion injury model. The phase I/II clinical trials of tolerogenic dendritic cell therapy have been conducted for kidney transplantation, so it is expected to have potential as a cell therapy for AKI in the future. There is still no established treatment for acute kidney injury (AKI), and the intervention of AKI remains limited to supportive treatments. Li et al. demonstrated the mechanism by which immune tolerance by dendritic cell ameliorates AKI in a mouse ischemia-reperfusion injury model. The phase I/II clinical trials of tolerogenic dendritic cell therapy have been conducted for kidney transplantation, so it is expected to have potential as a cell therapy for AKI in the future. Dendritic cells (DCs), discovered by Dr. Ralph M. Steinman and Dr. Zanvil A. Cohn in 1973, who awarded the Nobel Prize in Physiology or Medicine in 2011, are antigen-presenting cells and play a pivotal role in initiating immune response of acquired immunity. Precursor cells of DCs produced in the bone marrow are widely distributed in peripheral tissues as immature DCs. Immature DCs phagocytose antigens and, on activation, migrate to their lymph nodes, where they form major histocompatibility complex (MHC) molecules with antigen-derived peptides, which activate T cells and induce antigen-specific immune responses. DCs are not only more potent than other antigen-presenting cells but also have the ability to activate naïve T cells, induce differentiation of T cells by different costimulatory factors and induce immune tolerance in response to environmental factors. DCs with such diverse functions are formed from a heterogeneous cell population, consisting of multiple subsets with distinct phenotypes and functions. DC subsets can be broadly categorized into conventional DCs, which primarily promote immune responses and facilitate the differentiation and induction of antigen-specific T cells, and plasmacytoid DCs, which produce interferons during viral infections and contribute to the host defense in antiviral immunity. On the other hand, DCs with an immature phenotype, known as tolerogenic DCs (tolDCs), do not induce antigen-specific immune responses and instead exert immunosuppressive functions.1Lin J. Wang H. Liu C. et al.Dendritic cells: versatile players in renal transplantation.Front Immunol. 2021; 12654540Google Scholar DCs induce immune responses when they express high levels of MHC and costimulatory molecules CD80/CD86 and produce interleukin-12 (IL-12). On the other hand, when DCs exhibit low expression of MHC and costimulatory molecules and produce immunosuppressive cytokines such as IL-10, they induce immune tolerance.2Zahorchak A.F. Macedo C. Hamm D.E. et al.High PD-L1/CD86 MFI ratio and IL-10 secretion characterize human regulatory dendritic cells generated for clinical testing in organ transplantation.Cell Immunol. 2018; 323: 9-18Crossref PubMed Scopus (32) Google Scholar Therefore, tolDCs are regarded as promising therapeutic approaches for autoimmune diseases and allograft rejection in transplantation. In these diseases, the use of immunosuppressive drugs poses issues such as increased susceptibility to infections, side effects, and the risk of cancer. However, cellular therapy with tolDCs allows for a reduction in the amounts of immunosuppressive drugs used. Phase I/II clinical trials using tolDCs have been conducted for autoimmune diseases such as type 1 diabetes, rheumatoid arthritis, Crohn disease, multiple sclerosis, and liver and kidney transplantation.3Thomson A.W. Metes D.M. Ezzelarab M.B. et al.Regulatory dendritic cells for human organ transplantation.Transplant Rev (Orlando). 2019; 33: 130-136Crossref PubMed Scopus (38) Google Scholar,4Sawitzki B. Harden P.N. Reinke P. et al.Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials.Lancet. 2020; 395: 1627-1639Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar The generation of tolDCs used in ex vivo cell therapy involves inducing tolerance in bone marrow–derived progenitors (in animals) or CD14+ monocytes from peripheral blood mononuclear cells (in humans) using drugs such as vitamin D, IL-10, and dexamethasone. Many clinical trials have demonstrated high tolerability, with no observed treatment-related adverse reactions. Regarding kidney transplantation, it has been reported that infusion of donor-derived tolDC before transplantation interacts with cytotoxic T lymphocyte–associated antigen 4 present on host T cells, extending the survival period of the transplant.5Ezzelarab M.B. Lu L. Shufesky W.F. et al.Donor-derived regulatory dendritic cell infusion maintains donor-reactive CD4(+)CTLA4(hi) T cells in non-human primate renal allograft recipients treated with CD28 co-stimulation blockade.Front Immunol. 2018; 9: 250Crossref PubMed Scopus (21) Google Scholar However, the detailed mechanism is not yet fully understood. In the paper by Li et al.6Li J.S.Y. Robertson H. Trinh K. et al.Tolerogenic dendritic cells protect against acute kidney injury.Kidney Int. 2023; 104: 492-507Google Scholar in this issue, the immunoregulatory mechanisms of tolDCs were examined, particularly their potential to improve acute kidney injury (AKI), and their impact on kidney tubular epithelial cells (RTECs) was investigated (Figure 1). The authors evaluated the impact of ex vivo DC cell therapy on AKI using a bilateral kidney ischemia-reperfusion injury (IRI) mouse model. Initially, bone marrow–derived DCs and tolDCs (±lipopolysaccharide [LPS]) were induced through exposure to IL-10/1α,25-dihydroxyvitamin D3, which was previously used in clinical trials of liver and kidney transplantation. Analysis of expression markers confirmed the induction of tolDCs based on the downregulation of MHC II, CD80, CD86, an increase in PD-L1:CD86 mean fluorescence intensity ratio, and secretion of IL-10. Subsequently, in vitro coculture experiments were conducted with induced tolDCs and LPS-tolDCs in a noncontact manner with RTECs, followed by LPS-induced injury. The presence of LPS-tolDCs attenuated the impairment of tumor necrosis factor-α, lipocalin-2, and kidney injury molecule-1 in RTECs. The induced tolDCs and LPS-tolDCs exhibited not only inhibitory effects on lymphocyte proliferation but also an increase in PD-L1:CD86 mean fluorescence intensity ratio, enhanced IL-10 production, and suppression of IL-12p70 (proinflammatory factor) production. Furthermore, in vivo transplantation of tolDCs was performed in IRI mice. Administration of LPS-tolDCs before injury mitigated the elevation of serum creatinine levels, histological damage, and cell death caused by IRI. The kidney protective effect was also observed on the administration of allogenic-tolDCs, which were generated by conditioning DCs from mice of different strains. However, tolDCs without LPS stimulation did not show a significant protective effect against kidney injury. Both LPS-tolDCs and allogenic-tolDCs showed common changes in markers associated with tolerance induction. This result suggests the potential for organ protection even in the context of allogeneic transplantation. The authors suggested that the differential gene expression of chemokines such as CC-chemokine receptor 7 and CC-chemokine receptor 4, which were higher in LPS-tolDCs compared with unstimulated tolDCs, may contribute to the kidney-protective effect by facilitating the retention of LPS-tolDCs in the kidney. LPS-tolDCs exhibited higher immune activation and cytokine production pathways compared with tolDCs, suggesting that LPS-tolDCs possess the characteristics of alternatively activated DCs. Alternatively activated DCs are tolDCs that are selectively activated by inflammatory stimuli such as exposure to LPS. Although the effects of IL-10–conditioned tolDCs are modest, alternatively activated DCs exert significant effects in controlling inflammatory immune responses in vivo, particularly in protecting against graft-versus-host disease in transplantation.7Morelli A.E. Thomson A.W. Tolerogenic dendritic cells and the quest for transplant tolerance.Nat Rev Immunol. 2007; 7: 610-621Crossref PubMed Scopus (748) Google Scholar Furthermore, the spatial transcriptomics analysis revealed not only the suppression of proinflammatory cytokine expression after LPS-tolDC therapy but also the potential to alleviate tubular injury by promoting proximal tubular lipid oxidation and fatty acid metabolism. This result could explain the protective effect of tolDC on RTECs. Even more, these responses persisted even after depletion of recipient macrophages. What is interesting about this work by Li et al. is that they not only evaluated the impact of tolDC cell therapy on AKI for the first time but also demonstrated that the adoptive cell therapy of tolDCs had no influence on T cells or other myeloid cell populations, but rather it proved to suppress the damage to RTECs. There are reports suggesting that in renal IRI, proinflammatory cytokines and tumor necrosis factor derived from hypoxic endothelial cells can recruit DCs, and subsequently, hypoxia-inducible factor 1a induces the maturation of DCs, leading to impaired kidney function.8Jantsch J. Chakravortty D. Turza N. et al.Hypoxia and hypoxia-inducible factor-1 alpha modulate lipopolysaccharide-induced dendritic cell activation and function.J Immunol. 2008; 180: 4697-4705Crossref PubMed Scopus (318) Google Scholar,9Xu L. Sharkey D. Cantley L.G. Tubular GM-CSF promotes late MCP-1/CCR2-mediated fibrosis and inflammation after ischemia/reperfusion injury.J Am Soc Nephrol. 2019; 30: 1825-1840Crossref PubMed Scopus (72) Google Scholar Further investigation is needed regarding the effects of ex vivo tolDC cell therapy on renal resident DCs and other immune cells. On the other hand, spatial transcriptomic analysis currently has limited resolution, making it challenging to fully elucidate the precise spatial relationships and cell-cell interactions within the complex and diverse organ such as the kidney. In particular, the interaction between macrophages and proximal tubules, which is the focus of this study, requires further investigation beyond the findings of this experiment alone. Furthermore, in order to bring tolDC ex vivo cell therapy into actual clinical practice, further experiments in other AKI models are awaited. In summary, the work by Li et al. demonstrates that tolDC cell therapy can ameliorate kidney injury in a mouse model of IRI. The beneficial effects of tolDC therapy were also observed in in vitro experiments where tolDCs showed a reduction in kidney injury markers in RTECs without direct contact. Spatial transcriptomic analysis suggested that tolDCs might alleviate kidney injury by normalizing lipid oxidation and fatty acid metabolism pathways in the proximal tubules. The accumulation of further knowledge regarding the effectiveness and mechanisms of tolDCs in AKI has the potential for tolDC cell therapy to become a promising treatment for AKI. All the authors declared no competing interests. Tolerogenic dendritic cells protect against acute kidney injuryKidney InternationalVol. 104Issue 3PreviewIschemia reperfusion injury is a common precipitant of acute kidney injury that occurs following disrupted perfusion to the kidney. This includes blood loss and hemodynamic shock, as well as during retrieval for deceased donor kidney transplantation. Acute kidney injury is associated with adverse long-term clinical outcomes and requires effective interventions that can modify the disease process. Immunomodulatory cell therapies such as tolerogenic dendritic cells remain a promising tool, and here we tested the hypothesis that adoptively transferred tolerogenic dendritic cells can limit kidney injury. Full-Text PDF Open Access