Effects of tolerogenic dendritic cells generated by siRNA-mediated RelB silencing on immune defense and surveillance functions of T cells

Luo, Lei; Sun, Zhaolin; Qian, Fang; Huang, Shanying; Bai, Xiaoling; Luo, Guangheng

doi:10.1016/j.cellimm.2013.03.004

Cited by 9 publications

(7 citation statements)

References 37 publications

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“…The higher basal activation level of RelB in the BTZ adapted LC is in accordance with previous findings that nuclear RelB is crucial for DC development, maturation and antigen-presenting and T cell stimulatory capacities [45][46][47][48][49]. Indeed, ablation of RelB endows DC with tolerating abilities [50,51] and the absence of nuclear RelB in LC accounts for their reported ability for T cell tolerance induction [52]. Based on our findings, low-dose BTZ treatment may thus abolish DC/LC-mediated tolerization of effector T cells and support DC/LC-targeted tumor vaccination strategies.…”

Section: Discussionsupporting

confidence: 91%

Enhanced Dendritic Cell Development Through Long-Term Proteasome Inhibition

Ven¹,

Verbrugge

Al³

et al. 2018

J Mol Clin Med.

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Bortezomib (BTZ) is a potent and reversible proteasome inhibitor which has shown efficacy in the treatment of multiple myeloma. BTZ also affects NF-κB activity, however, the same mechanisms through which it curtails malignant cell proliferation may also compromise antitumor immunity. As dendritic cells (DC) play a vital role in the elicitation and maintenance of antitumor immunity, we herein studied the long-term effects of BTZ on human DC development and function. The CD34 + MUTZ-3 cell line, stably transduced with human telomerase reverse transcriptase (hTERT), was employed as a sustainable model to study human steady-state DC development and was grown in the presence of gradually increasing BTZ concentrations over a period of 4 months. The resultant BTZ-adapted cells were prospectively assessed for their ability to develop into mature Langerhans cells (LC). Long-term exposure to BTZ (>10 months) at a clinically relevant and apoptosis-inducing concentration (10 nM) provoked spontaneous differentiation in surviving precursors, evidenced by increased expression levels of CD14, TNF receptors and immunoproteasome subunits. Cytokine-dependent differentiation was also enhanced, resulting in increased numbers of mature DC with higher levels of co-stimulatory molecules and an increased capacity for T cell induction. Assessment of nuclear NF-κB subunit levels provided evidence for a role of canonical RelB/p50 activation in the enhanced DC differentiation and maturation established through prolonged BTZ exposure. We conclude that long-term treatment with low dose BTZ is consistent with DCdependent induction of antitumor immunity.

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Section: Discussionsupporting

confidence: 91%

Enhanced Dendritic Cell Development Through Long-Term Proteasome Inhibition

Ven¹,

Verbrugge

Al³

et al. 2018

J Mol Clin Med.

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“…The RelB subunit of NF-κB controls DCs maturation and may be therapeutically targeted to manipulate the T cell response in disease. Several groups have reported that RelB promoted DC activation, and RelB-silenced DCs could induce donor-specific hypo-responsiveness and impair immune functions of T cells [28,34]. The tumor microenvironment-derived immunosuppressive cytokines (VEGF, TGF, IL-10 et al) down-regulate the expression levels of chemokines, adhesion molecule and costimulatory molecules by suppressing expression of NF-κB [35,36].…”

Section: Discussionmentioning

confidence: 99%

Investigations of the functional states of dendritic cells under different conditioned microenvironments by Fourier transformed infrared spectroscopy

Dong¹,

Long

Xu³

et al. 2014

BioMed Eng OnLine

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BackgroundDendritic cells are potent and specialized antigen presenting cells, which play a crucial role in initiating and amplifying both the innate and adaptive immune responses. The dendritic cell-based vaccination against cancer has been clinically achieved promising successes. But there are still many challenges in its clinical application, especially for how to identify the functional states.MethodsThe CD14+ monocytes were isolated from human peripheral blood after plastic adherence and purified to approximately 98% with cocktail immunomagnetic beads. The immature dendritic cells and mature dendritic cells were induced by traditional protocols. The resulting dendritic cells were cocultured with normal cells and cancer cells. The functional state of dendritic cells including immature dendritic cells (imDCs) and mature dendritic cells (mDCs) under different conditioned microenvironments were investigated by Fourier transformed infrared spectroscopy (FTIR) and molecular biological methods.ResultsThe results of Fourier transformed infrared spectroscopy showed that the gene transcription activity and energy states of dendritic cells were specifically suppressed by tumor cells (P < 0.05 or 0.01). The expression levels of NF-kappa B (NF-κB) in dendritic cells were also specifically inhibited by tumor-derived factors (P < 0.05 or 0.01). Moreover, the ratios of absorption intensities of Fourier transformed infrared spectroscopy at given wave numbers were closely correlated with the expression levels of NF-κB (R2:0.69 and R2:0.81, respectively).ConclusionOur results confirmed that the ratios of absorption intensities of Fourier transformed infrared spectroscopy at given wave numbers were positively correlated with the expression levels of NF-κB, suggesting that Fourier transformed infrared spectroscopy technology could be clinically applied to identify the functional states of dendritic cell when performing dendritic cell-based vaccination. It’s significant for the simplification and standardization of dendritic cell-based vaccination clinical preparation protocols.

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“…29 RelB-silenced DCs were previously demonstrated to have a less mature phenotype with expression of low-level co-stimulatory molecules and exhibited inhibitory effects on mixed lymphocyte reaction and allogeneic immune responses. 30,31 RelB shRNAsilenced DCs also showed immunomodulatory effects in vivo in the prevention of graft rejection in murine heart 30 and liver transplantation 32 and in the treatment of a murine model of myasthenia gravis. 33,34 Here, we generated semi-mature MRL/MpJ RelB-shRNA DCs that expressed lower levels of co-stimulatory molecules compared with SC-shRNA DCs.…”

Section: Discussionmentioning

confidence: 99%

“…It is an important rationale for cell‐based therapy to generate semi‐mature DCs with a stable phenotype to avoid conversion to immunogenic status under inflammatory environments in vivo . RelB‐silenced DCs were previously demonstrated to have a less mature phenotype with expression of low‐level co‐stimulatory molecules and exhibited inhibitory effects on mixed lymphocyte reaction and allogeneic immune responses . RelB shRNA‐silenced DCs also showed immunomodulatory effects in vivo in the prevention of graft rejection in murine heart and liver transplantation and in the treatment of a murine model of myasthenia gravis …”

Section: Discussionmentioning

confidence: 99%

Rel B‐modified dendritic cells possess tolerogenic phenotype and functions on lupus splenic lymphocytes in vitro

Chan

et al. 2016

Immunology

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SummarySystemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by high morbidity and mortality and its treatment remains challenging. Dendritic cells (DCs) have been shown to participate in the initiation and perpetuation of lupus pathogenesis and the DCs that can induce tolerogenicity appear as potential cell‐based therapy in this condition. In this study, we examined the in vitro tolerogenic properties of bone‐marrow derived DCs (BMDCs) in the murine lupus setting. We used lentiviral transduction of RelB‐silencing short hairpin RNA to modify the expression of RelB, a key transcription factor regulating DC maturation, in BMDCs from MRL/MpJ mice. Tolerogenic properties of RelB‐modified DCs were compared with scrambled control (SC) ‐modified DCs. RelB expression was found to be significantly reduced in RelB‐modified DCs derived from MRL/MpJ mice, wild‐type of the same genetic background as MRL/lpr lupus‐prone mice. These MRL/MpJ RelB‐modified DCs displayed semi‐mature phenotype with expression of lower levels of co‐stimulatory molecules compared with SC‐modified DCs. RelB‐modified DCs were found to be low producers of interleukin‐12p70 (IL‐12p70) and could induce hyporesponsiveness of splenic T cells from MRL/MpJ and MRL/lpr mice. Furthermore, they down‐regulated interferon‐γ expression and induced IL‐10‐producing T cells in MRL/MpJ splenocytes, and attenuated interferon‐γ and IL‐17 expression in MRL/lpr splenic CD4+ lymphocytes. Splenocytes primed by RelB‐modified DCs demonstrated antigen‐specific suppressive effects on allogeneic splenocytes. In conclusion, RelB‐silencing in DCs generates DCs of tolerogenic properties with immunomodulatory function and appears as potential option of cell‐targeted therapy.

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Effects of tolerogenic dendritic cells generated by siRNA-mediated RelB silencing on immune defense and surveillance functions of T cells

Cited by 9 publications

References 37 publications

Enhanced Dendritic Cell Development Through Long-Term Proteasome Inhibition

Enhanced Dendritic Cell Development Through Long-Term Proteasome Inhibition

Investigations of the functional states of dendritic cells under different conditioned microenvironments by Fourier transformed infrared spectroscopy

Rel B‐modified dendritic cells possess tolerogenic phenotype and functions on lupus splenic lymphocytes in vitro

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