Therapeutic effect of tolerogenic dendritic cells in established collagen‐induced arthritis is associated with a reduction in Th17 responses

Stoop, Jeroen N.; Harry, Rachel A.; Delwig, Alexei von; Isaacs, John D.; Robinson, John H.; Hilkens, Catharien M. U.

doi:10.1002/art.27756

Cited by 123 publications

(122 citation statements)

References 52 publications

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“…DC have the homeostatic function of promoting immunological tolerance to self‐antigens thereby preventing the development of autoimmune disorders 65. Both pre‐clinical and clinical studies have shown that adoptively transferred DC have potent immunosuppressive properties 14, 66, 67, 68. However, there is a risk that DC placed in the pro‐inflammatory environment of the host with active autoimmune disease would convert to activated self‐antigen‐presenting DC, promoting immunity rather than tolerance, thereby worsening the disease.…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide‐primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms

et al. 2016

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SummaryExposure of bone‐marrow‐derived dendritic cells (BMDC) to high‐dose ultrapure lipopolysaccharide for 24 hr (LPS‐primed BMDC) enhances their potency in preventing inter‐photoreceptor retinoid binding protein: complete Freund's adjuvant‐induced experimental autoimmune uveoretinitis (EAU). LPS‐primed BMDC are refractory to further exposure to LPS (= endotoxin tolerance), evidenced here by decreased phosphorylation of TANK‐binding kinase 1, interferon regulatory factor 3 (IRF3), c‐Jun N‐terminal kinase and p38 mitogen‐activated protein kinase as well as impaired nuclear translocation of nuclear factor κB (NF‐κB) and IRF3, resulting in reduced tumour necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), IL‐12 and interferon‐β secretion. LPS‐primed BMDC also show reduced surface expression of Toll‐like receptor‐4 and up‐regulation of CD14, followed by increased apoptosis, mediated via nuclear factor of activated T cells (NFATc)‐2 signalling. LPS‐primed BMDC are not only homotolerant to LPS but are heterotolerant to alternative pathogen‐associated molecular pattern ligands, such as mycobacterial protein extract (Mycobacterium tuberculosis). Specifically, while M. tuberculosis protein extract induces secretion of IL‐1β, TNF‐α and IL‐6 in unprimed BMDC, LPS‐primed BMDC fail to secrete these cytokines in response to M. tuberculosis. We propose that LPS priming of BMDC, by exposure to high doses of LPS for 24 hr, stabilizes their tolerogenicity rather than promoting immunogenicity, and does so by multiple mechanisms, namely (i) generation of tolerogenic apoptotic BMDC through CD14:NFATc signalling; (ii) reduction of NF‐κB and IRF3 signalling and downstream pro‐inflammatory cytokine production; and (iii) blockade of inflammasome activation.

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Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide‐primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms

et al. 2016

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“…Similarly, expression of glucocorticoid-inducible TNFR (GITR) has been shown to occur in protective Treg cells (22). Induction of smDC has to date been experimentally achieved by DC stimulation under diminished inflammatory environments, such that are achieved by added vitamin D (23,24), , estrogen (25), MyD88 inhibitors (26), and IL-10 (27).…”

Section: Endritic Cells (Dc) Undergo Transition From Immature DCmentioning

confidence: 99%

α-1 Antitrypsin Promotes Semimature, IL-10–Producing and Readily Migrating Tolerogenic Dendritic Cells

Ozeri

Mizrahi

Shahaf

et al. 2012

The Journal of Immunology

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Tolerogenic IL-10–positive CCR7-positive dendritic cells (DC) promote T regulatory (Treg) cell differentiation upon CCR7-dependent migration to draining lymph nodes (DLN). Indeed, in human DC deficiencies, Treg levels are low. α-1 antitrypsin (AAT) has been shown to reduce inflammatory markers, promote a semimature LPS-induced DC phenotype, facilitate Treg expansion, and protect pancreatic islets from alloimmune and autoimmune responses in mice. However, the mechanism behind these activities of AAT is poorly understood. In this study, we examine interactions among DC, CD4+ T cells, and AAT in vitro and in vivo. IL-1β/IFN-γ–mediated DC maturation and effect on Treg development were examined using OT-II cells and human AAT (0.5 mg/ml). CCL19/21-dependent migration of isolated DC and resident islet DC was assessed, and CCR7 surface levels were examined. Migration toward DLN was evaluated by FITC skin painting, transgenic GFP skin tissue grafting, and footpad DC injection. AAT-treated stimulated DC displayed reduced MHC class II, CD40, CD86, and IL-6, but produced more IL-10 and maintained inducible CCR7. Upon exposure of CD4+ T cells to OVA-loaded AAT-treated DC, 2.7-fold more Foxp3+ Treg cells were obtained. AAT-treated cells displayed enhanced chemokine-dependent migration and low surface CD40. Under AAT treatment (60 mg/kg), DLN contained twice more fluorescence after FITC skin painting and twice more donor DC after footpad injection, whereas migrating DC expressed less CD40, MHC class II, and CD86. Intracellular DC IL-10 was 2-fold higher in the AAT group. Taken together, these results suggest that inducible functional CCR7 is maintained during AAT-mediated anti-inflammatory conditions. Further studies are required to elucidate the mechanism behind the favorable tolerogenic activities of AAT.

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“…+ Treg cells. Immature DCs are considered to be prototypic tolerogenic DCs due to their poor T cell stimulatory capacity (40). Immature DCs have therefore been utilized to induce immunosuppression in mammals with specific malignancies or autoimmune disease, as well as following transplantation (41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

Effect of immune tolerance induced by immature dendritic cells and CTLA4-Ig on systemic lupus erythematosus: An inï¿½vivo study

et al. 2018

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Abstract. Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease in which tissue damage is caused by autoantibodies. The induction of specific immune tolerance, including the utilization of immune regulatory cells, may enhance the therapeutic effects of organ transplantation in patients with SLE. Furthermore, inhibiting immune responses has been reported to be an effective treatment for SLE. However, few studies have explored the association between an increased immune tolerance and a decreased immune response in SLE treatment. Dendritic cells (DCs), which are highly efficient antigen-presenting cells, are able to induce specific tolerance, while cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA4-Ig) inhibits the immune response. In the present study, interleukin (IL)-10-treated DCs and CTLA4-Ig were administered to mice with SLE alone or in combination and the therapeutic effects were investigated. IL-10 was added into the culture medium of bone marrow-derived DCs to prevent them from differentiating into mature cells. Low levels of major histocompatibility complex II, cluster of differentiation (CD)40, CD80 and CD86 were detected, which indicated that the immature state of DCs was maintained. IL-10-treated DCs were subsequently injected into the caudal vein of B6.MRL-Fas lpr /J lupus mice, which are an established animal model of SLE. To amplify the tolerance effect, mice were simultaneously injected with CTLA4-Ig. Compared with the IL-10-treated DC and CTLA4-Ig groups, combined treatment with IL-10-treated DCs and CTLA4-Ig strongly induced immune tolerance in mice with SLE, as indicated by the significantly reduced levels of urine protein, anti-nuclear antibody, double-stranded DNA and IL-17A. A significant decrease in the proportion of T helper cells and an increase in the proportion of CD4 + forkhead box protein P3 + Treg cells was also observed, further confirming the induction of immune tolerance. These results suggest that combined treatment with IL-10-DCs and CTLA4-Ig may be a promising novel therapeutic strategy for the treatment of SLE.

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Therapeutic effect of tolerogenic dendritic cells in established collagen‐induced arthritis is associated with a reduction in Th17 responses

Cited by 123 publications

References 52 publications

Lipopolysaccharide‐primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms

Lipopolysaccharide‐primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms

α-1 Antitrypsin Promotes Semimature, IL-10–Producing and Readily Migrating Tolerogenic Dendritic Cells

Effect of immune tolerance induced by immature dendritic cells and CTLA4-Ig on systemic lupus erythematosus: An inï¿½vivo study

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