Tolerogenic dendritic cells produced by lentiviral-mediated CD40- and interleukin-23p19-specific shRNA can ameliorate experimental autoimmune encephalomyelitis by suppressing T helper type 17 cells

Kalantari, Tahereh; Karimi, Mohammad Hossein; Ćirić, Bogoljub; Yan, Yaping; Rostami, Abdolmohamad; Kamali-Sarvestani, Eskandar

doi:10.1111/cei.12266

Cited by 19 publications

(14 citation statements)

References 43 publications

(51 reference statements)

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“…Moreover, ApoCell‐loaded tolDCs derived from SLE monocytes secreted lower levels of IL‐6 and IL‐12p70 than controls after LPS challenge. Conversely, ApoCell‐loaded tolDCs stimulated with LPS showed no differences in IL‐10 production compared with mDCs, which is not consistent with previous reports . However, there are data showing that functional tolDCs do not secrete higher levels of IL‐10, but the production of pro‐inflammatory cytokines is significantly impaired instead .…”

Section: Discussioncontrasting

confidence: 85%

Autologous tolerogenic dendritic cells derived from monocytes of systemic lupus erythematosus patients and healthy donors show a stable and immunosuppressive phenotype

et al. 2017

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Systemic lupus erythematosus (SLE) is an autoimmune disease with unrestrained T-cell and B-cell activity towards self-antigens. Evidence shows that apoptotic cells (ApoCells) trigger an autoreactive response against nuclear antigens in susceptible individuals. In this study, we focus on generating and characterizing tolerogenic dendritic cells (tolDCs) to restore tolerance to ApoCells. Monocyte-derived dendritic cells (DCs) from healthy controls and patients with SLE were treated with dexamethasone and rosiglitazone to induce tolDCs. Autologous apoptotic lymphocytes generated by UV irradiation were given to tolDCs as a source of self-antigens. Lipopolysaccharide (LPS) was used as a maturation stimulus to induce the expression of co-stimulatory molecules and secretion of cytokines. TolDCs generated from patients with SLE showed a reduced expression of co-stimulatory molecules after LPS stimulation compared with mature DCs. The same phenomenon was observed in tolDCs treated with ApoCells and LPS. In addition, ApoCell-loaded tolDCs stimulated with LPS secreted lower levels of interleukin-6 (IL-6) and IL-12p70 than mature DCs without differences in IL-10 secretion. The functionality of tolDCs was assessed by their capacity to prime allogeneic T cells. TolDCs displayed suppressor properties as demonstrated by a significantly reduced capacity to induce allogeneic T-cell proliferation and activation. ApoCell-loaded tolDCs generated from SLE monocytes have a stable immature/tolerogenic phenotype that can modulate CD4 T-cell activation. These properties make them suitable for an antigen-specific immunotherapy for SLE.

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Section: Discussioncontrasting

confidence: 85%

Autologous tolerogenic dendritic cells derived from monocytes of systemic lupus erythematosus patients and healthy donors show a stable and immunosuppressive phenotype

et al. 2017

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“…Therapeutic approaches such as IL-23p19-specific mAbs, antisense oligos against IL-23 mRNA, and sIL-23R have shown to downregulate the expression of IL-23 in MS models. 28,89,92 However, further research should be done in the extracted cells of patients with MS to elucidate the role of these potential treatments in disease progression to develop effective clinical versions to use as treatments. In addition, further study into the IL-23R-STAT3 pathway and its role in IL-17 and IL-23R regulation is a promising avenue that could lead to improved treatment of MS. 92,98 Multiple sclerosis onset has also been linked to the B7/Tcell costimulatory pathway, particularly the B7-CD28/ CTLA-4 costimulatory pathway.…”

Section: Discussionmentioning

confidence: 99%

“…When transduced, BMDCs are co-cultured with CD4 + T cells of EAE mice, and a decrease in T-cell proliferation to the pathogenic subset can be observed. 89 In addition, IL-23p19-specific shRNA transduction appears to aid in the maturation of BMDCs toward the tolerogenic subset, increasing IL-10 production, whereas the production of IL-6, IL-12, and IFN-γ is greatly reduced. 90 Unfortunately, despite the observed success of IL-23-specific antisense treatment, there have not been further studies or any clinical trials that test this specific therapeutic approach.…”

Section: Il-23 and Msmentioning

confidence: 99%

Involvement of Immune Regulation in Multiple Sclerosis

Spagnuolo

Piavis

Williams

2017

Immunol Immunogenet Insights

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Multiple sclerosis (MS) is a neurodegenerative disease characterized by neuroinflammation and demyelination that results in axon loss. Multiple sclerosis has been shown to be the result of an autoimmune response caused by a mixture of genetic and environmental factors. Dendritic cells are prominent antigen-presenting cells that interact with various molecules to regulate the immune system. The dysfunction of various features of immune regulation, including interleukins (ILs), CD4 + T cells, and suppressor of cytokine signaling (SOCS1), has been implicated in the pathogenesis of MS. T cells, particularly through the malfunction of B7-costimulatory pathways, have been shown to affect the progression of the disease. SOCS1 is important in regulating the function of T cells through its interactions with other nearby genes, especially CLEC16A, with abnormal decreases in SOCS1 expression leading to the exhibition of MS symptoms. The activation of IL-23 receptors on CD4 + T cells is pivotal to their differentiation into pathogenic T H 17 cells. Several promising compounds that downregulate gene expression of IL-23 and IL-23R have been discovered but require further investigation for efficacy and safety. Given their role in the severity and progression of MS, therapies that decrease these dysregulations may ultimately decrease symptoms and in turn improve patients' quality of life.

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“…Tolerogenic DCs generated using these methods demonstrated immunomodulatory effects of induction of T‐cell anergy, expansion of natural Treg cells, or differentiation of peripheral Treg cells . Tolerogenic DCs have been shown to have potential therapeutic uses in murine models of some autoimmune diseases such as collagen‐induced arthritis, experimental autoimmune encephalomyelitis, myasthenia gravis and antiphospholipid syndrome . As DCs play an important role in the initiation and perpetuation of disease pathogenesis in SLE, tolerogenic DCs appear to be a potential cell‐based therapy in this condition …”

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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Tolerogenic dendritic cells produced by lentiviral-mediated CD40- and interleukin-23p19-specific shRNA can ameliorate experimental autoimmune encephalomyelitis by suppressing T helper type 17 cells

Cited by 19 publications

References 43 publications

Autologous tolerogenic dendritic cells derived from monocytes of systemic lupus erythematosus patients and healthy donors show a stable and immunosuppressive phenotype

Autologous tolerogenic dendritic cells derived from monocytes of systemic lupus erythematosus patients and healthy donors show a stable and immunosuppressive phenotype

Involvement of Immune Regulation in Multiple Sclerosis

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

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