Tolerogenic dendritic cells protect against acute kidney injury

Abstract

Ischemia 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. The phenotypic and genomic signatures of bone marrow–derived syngeneic or allogeneic, Vitamin-D3/IL-10–conditioned tolerogenic dendritic cells were assessed. These cells were characterized by high PD-L1:CD86, elevated IL-10, restricted IL-12p70 secretion and a suppressed transcriptomic inflammatory profile. When infused systemically, these cells successfully abrogated kidney injury without modifying infiltrating inflammatory cell populations. They also provided protection against ischemia reperfusion injury in mice pre-treated with liposomal clodronate, suggesting the process was regulated by live, rather than reprocessed cells. Co-culture experiments and spatial transcriptomic analysis confirmed reduced kidney tubular epithelial cell injury. Thus, our data provide strong evidence that peri-operatively administered tolerogenic dendritic cells have the ability to protect against acute kidney injury and warrants further exploration as a therapeutic option. This technology may provide a clinical advantage for bench-to-bedside translation to affect patient outcomes. Ischemia 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. The phenotypic and genomic signatures of bone marrow–derived syngeneic or allogeneic, Vitamin-D3/IL-10–conditioned tolerogenic dendritic cells were assessed. These cells were characterized by high PD-L1:CD86, elevated IL-10, restricted IL-12p70 secretion and a suppressed transcriptomic inflammatory profile. When infused systemically, these cells successfully abrogated kidney injury without modifying infiltrating inflammatory cell populations. They also provided protection against ischemia reperfusion injury in mice pre-treated with liposomal clodronate, suggesting the process was regulated by live, rather than reprocessed cells. Co-culture experiments and spatial transcriptomic analysis confirmed reduced kidney tubular epithelial cell injury. Thus, our data provide strong evidence that peri-operatively administered tolerogenic dendritic cells have the ability to protect against acute kidney injury and warrants further exploration as a therapeutic option. This technology may provide a clinical advantage for bench-to-bedside translation to affect patient outcomes. Translational StatementDespite the ability to predict and identify acute kidney injury (AKI), clinicians can only offer supportive care and dialysis when the problem arises. Herein, we demonstrate the potential use of tolerogenic dendritic cells (tolDCs), demonstrating that these cells can alter the early immunopathology and severity of AKI. There is an impetus to further explore the mechanistic role of tolDCs in AKI and repair, and evidence from phase I/II clinical trials for transplant tolerance suggests that tolDCs are safe. This provides tolDCs with an immediate clinical advantage for bench-to-bedside translation to impact patient outcomes. Despite the ability to predict and identify acute kidney injury (AKI), clinicians can only offer supportive care and dialysis when the problem arises. Herein, we demonstrate the potential use of tolerogenic dendritic cells (tolDCs), demonstrating that these cells can alter the early immunopathology and severity of AKI. There is an impetus to further explore the mechanistic role of tolDCs in AKI and repair, and evidence from phase I/II clinical trials for transplant tolerance suggests that tolDCs are safe. This provides tolDCs with an immediate clinical advantage for bench-to-bedside translation to impact patient outcomes. Acute kidney injury (AKI) is a global disorder,1Susantitaphong P. Cruz D.N. Cerda J. et al.World incidence of AKI: a meta-analysis.Clin J Am Soc Nephrol. 2013; 8: 1482-1493Crossref PubMed Scopus (979) Google Scholar and epidemiological evidence clearly establishes that AKI is neither benign nor self-limited, and survivors are confronted with an increased risk of chronic kidney disease,2Chawla L.S. Eggers P.W. Star R.A. Kimmel P.L. Acute kidney injury and chronic kidney disease as interconnected syndromes.N Engl J Med. 2014; 371: 58-66Crossref PubMed Scopus (1346) Google Scholar infection,3Griffin B.R. You Z. Holmen J. et al.Incident infection following acute kidney injury with recovery to baseline creatinine: a propensity score matched analysis.PloS One. 2019; 14e0217935Crossref Scopus (16) Google Scholar cardiovascular morbidity,4Chawla L.S. Amdur R.L. 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Academic Press, 2021: 1-42Crossref Scopus (2) Google Scholar Dendritic cells (DCs) are potent antigen-processing/presenting cells that are recruited and activated into mature DCs by proinflammatory cytokines and danger-associated molecular patterns released by injured/dying renal tubular epithelial cells (RTECs).15Dong X. Swaminathan S. Bachman L.A. et al.Resident dendritic cells are the predominant TNF-secreting cell in early renal ischemia-reperfusion injury.Kidney Int. 2007; 71: 619-628Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar Mature DCs generate effector T-cell responses in the tubulointerstitium by presenting nonfilterable proteins,16Macconi D. Chiabrando C. Schiarea S. et al.Proteasomal processing of albumin by renal dendritic cells generates antigenic peptides.J Am Soc Nephrol. 2009; 20: 123-130Crossref PubMed Scopus (89) Google Scholar but the evidence for a direct effect of DCs on RTECs that is independent of changes in the T-cell subset or function is lacking, as is a comprehensive understanding of parenchymal molecular pathways changed in response to DC fluxes that occur in AKI. DCs can also be pharmacologically or genetically manipulated in vitro to generate a tolerogenic, or stable, semimature (alternatively activated) phenotype.17Morelli A.E. Thomson A.W. Tolerogenic dendritic cells and the quest for transplant tolerance.Nature Rev Immunol. 2007; 7: 610-621Crossref PubMed Scopus (757) Google Scholar Tolerogenic DCs (tolDCs) display low-level costimulatory molecule expression and enhanced anti-inflammatory cytokine secretion; they are capable of subverting effector T-cell responses and inducing regulatory T cells. Renewed interest in cellular therapies has facilitated successful translation of preclinical studies to phase I/II clinical trials for reduced dependence on immunosuppressive drugs or tolerance in autoimmune disease and transplantation, with promising feasibility and safety data.18Li J. Thomson A.W. Rogers N.M. Myeloid and mesenchymal stem cell therapies for solid organ transplant tolerance.Transplantation. 2021; 105: e303-e321Crossref PubMed Scopus (7) Google Scholar, 19Zahorchak A.F. Kean L.S. Tokita D. et al.Infusion of stably immature monocyte-derived dendritic cells plus CTLA4Ig modulates alloimmune reactivity in rhesus macaques.Transplantation. 2007; 84: 196-206Crossref PubMed Scopus (47) Google Scholar, 20Sawitzki B. Harden P.N. 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A. and tolerogenic dendritic cells in regulatory J 2021; PubMed Scopus Google Scholar The of therapy from the of and in transplantation are characterized by to a of to The of tolDCs to clinical of antigenic may be anti-inflammatory of tolDCs a potential therapy for AKI, is for a disease with effective than but has preclinical we tolDCs limit in AKI, of and provided that an understanding of and AKI. and mice from were in our for with and were in with the for the care and use of for by the and of mice bone cell and with cell were in DC tolDCs were with the of and to DC on of cytokines were was in on cell on for the marrow–derived DC and were to cells in studies the and were in and with and with were the with and and data analysis was in The of IL-10, and in cell was by and was by a as the The of or tolDCs was tested in a after with with were to and of and mice was the with is available in RTECs were as N.M. et renal tubular epithelial cell and following renal ischemia Int. 2016; Full Text Full Text PDF PubMed Scopus Google Scholar were the and with and The cell was in the and on and were and were to the with DC or tolDCs or and to for was to the and RTECs and after to mice were to with for ischemia-reperfusion injury facilitated to the renal for and with cell mice syngeneic or cells in a approach on the or of mice of or by by cell therapy and renal mice were after with of blood by and kidney in or in and were by a in were and with and by N.M. et renal tubular epithelial cell and following renal ischemia Int. 2016; Full Text Full Text PDF PubMed Scopus Google Scholar were for of acute tubular on tubular cell and were and with the in cell The of cells in a were of and were with and The of cells were were by independent from were with with cell and of cells were the was tolDCs or with of on the of The and were into a cell and with and for was from or cell the a and the was in the with and from were the with expression to the and as the was on kidney of X. et of the molecular and of Google Scholar and analysis is in the are as were with the for between or analysis of between of was and tolDCs by to and and and expression was for and tolDCs of These were after in and tolDCs and and The in major and expression was in with but expression was in with The a of was for and and T-cell in response to was abrogated in the of tolDCs or and effect was when the to cell was or when only were to the and a transcriptomic J. et analysis a tolerogenic dendritic cell Immunol. 2021; Scopus Google Scholar and on and to potential genomic of our cells. 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