Novel Vaccination for Allergy through Gene Silencing of CD40 Using Small Interfering RNA

Suzuki, Motohiko; Zheng, Xiufen; Zhang, Xusheng; Vladau, Costin; Ichim, Thomas E.; Sun, Hongtao; Min, Lisa; García, Bertha; Min, Wei‐Ping

doi:10.4049/jimmunol.180.12.8461

Cited by 30 publications

(42 citation statements)

References 50 publications

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“…Mechanistically, calcitriol also has been shown through mediate effects through inhibition of NFkB (15). We have previously demonstrated that RNA interference may be evoked in DCs with short interfering RNA (siRNA) without induction of DC maturation or alteration of viability (16)(17)(18). These findings show that suppression of genes such as IL-12 p35, CD40, and RelB could endow DCs with the ability to inhibit immune responses both in vitro and in vivo (17,18).…”

Section: Endritic Cells (Dcs) Offer An Ideal Platform For Ag Deliverymentioning

confidence: 95%

“…We have previously demonstrated that RNA interference may be evoked in DCs with short interfering RNA (siRNA) without induction of DC maturation or alteration of viability (16)(17)(18). These findings show that suppression of genes such as IL-12 p35, CD40, and RelB could endow DCs with the ability to inhibit immune responses both in vitro and in vivo (17,18). For example, administration of DCs pulsed with the model Ag OVA followed by subsequent silencing of IL-12 p35 led to a Th2 shift in Ag-specific recall response (16).…”

Section: Endritic Cells (Dcs) Offer An Ideal Platform For Ag Deliverymentioning

confidence: 99%

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Treatment of Autoimmune Arthritis Using RNA Interference-Modulated Dendritic Cells

Zheng

Suzuki

Ichim³

et al. 2010

The Journal of Immunology

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Dendritic cells (DCs) have a dual ability to either stimulate or suppress immunity, which is primarily associated with the expression of costimulatory molecules. Ag-loaded DCs have shown encouraging clinical results for treating cancer and infectious diseases; however, the use of these cells as a means of suppressing immune responses is only recently being explored. Here, we describe the induction of RNA interference through administering short interfering RNA (siRNA) as a means of specifically generating tolerogenic DCs. Knockdown of CD40, CD80, and CD86, prior to loading DCs with the arthritogenic Ag collagen II, led to a population of cells that could effectively suppress onset of collagen-induced arthritis. Maximum benefits were observed when all three genes were concurrently silenced. Disease suppression was associated with inhibition of collagen II-specific Ab production and suppression of T cell recall responses. Downregulation of IL-2, IFN-γ, TNF-α, and IL-17 and increased FoxP3+ cells with regulatory activity were observed in collagen-induced arthritis mice treated with siRNA-transfected DCs. Collectively, these data support the use of ex vivo gene manipulation in DCs using siRNA to generate tailor-made tolerogenic vaccines for treating autoimmunity.

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Section: Endritic Cells (Dcs) Offer An Ideal Platform For Ag Deliverymentioning

confidence: 95%

Section: Endritic Cells (Dcs) Offer An Ideal Platform For Ag Deliverymentioning

confidence: 99%

Treatment of Autoimmune Arthritis Using RNA Interference-Modulated Dendritic Cells

Zheng

Suzuki

Ichim³

et al. 2010

The Journal of Immunology

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“…RNA interference is a posttranscriptional mechanism of gene silencing, in which 19-23 nucleotide double-stranded RNA duplexes promote specific endonucleolytic cleavage of mRNA targets called small interfering RNA (siRNA) as described in Raoul et al (2005) and Suzuki et al (2008). Gene silencing using siRNA is an extremely efficient, specific, long-lasting, and simple method for blocking the expression of target genes as described by Hill et al (2003).…”

Section: Introductionmentioning

confidence: 99%

Experience with lentivirus-mediated CD40 gene silencing in a mouse model of Graves' disease

Shi²,

Wu³

et al. 2010

Journal of Endocrinology

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CD40 plays an important role in the pathogenesis of Graves' disease (GD). Inhibition of CD40 expression may be a promising treatment for GD. In this study, we used an animal model to investigate whether lentivirus expressing siRNA for CD40 (LV-CD40-siRNA) could be useful for the therapy of GD. BALB/c mice were injected with PBS alone (PBS group), negative lentivirus (control siRNA group), or LV-CD40-siRNA (CD40 siRNA group), 3 days before being treated with adenovirus expressing human TSHR A subunit (Ad-TSHR289) three times at 3-week intervals to induce GD model. Sera thyroxine (T 4 ) levels were assayed by RIA. The expression of CD40 was detected at the mRNA level by real-time PCR and protein level by flow cytometry. The expression of CD40, CD80, and CD86 was significantly decreased in the CD40 siRNA group (P!0 . 05), while FOXP3 expression was increased compared to the control siRNA group (PZ0 . 05). Mean T 4 levels were decreased 14% in the CD40 siRNA group compared to the control siRNA group. The rate of disease induction was similar among the three groups injected with Ad-TSHR289. LV-CD40-siRNA is a useful tool to inhibit the expression of CD40 in vivo, but it cannot decrease the incidence of hyperthyroidism in a limited period of time.

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“…The activation and differentiation of T cells play an important role in the pathogenesis of myocarditis. 1,40,41) First, we demonstrated that Th1-type cytokine production was markedly increased in the negative control group, and that this cytokine production was significantly suppressed in myocarditis rats after CD40 siRNA treatment. However, production of Th2-type cytokines was higher in the CD40 siRNA group compared with the negative control group.…”

Section: Discussionmentioning

confidence: 99%

Attenuation of Experimental Autoimmune Myocarditis by si-RNA Mediated CD40 Silencing

Gong

Han

Zou³

et al. 2014

Int. Heart J.

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SummaryCD40 plays an important role in the pathogenesis of myocarditis, and inhibition of CD40 expression could be a promising treatment for myocarditis. In this study, we used an animal model, experimental autoimmune myocarditis (EAM), to investigate whether CD40 siRNA could be exploited for myocarditis therapy.Lewis rats were immunized with purified porcine cardiac myosin to induce EAM or were injected with phosphatebuffered saline (PBS) alone (PBS group), scrambled small interfering RNA (siRNA) (negative control group), or CD40-siRNA (CD40 siRNA group).CD40 siRNA treatment suppressed the increase in heart weight/body weight ratio, and attenuated the severity of myocardial lesions. Cytokine production, including Th1-type cytokines, was significantly suppressed in rats with myocarditis after CD40 siRNA treatment; however, production of Th2-type cytokines was higher. Specific knockdown of CD40 in EAM rats resulted in increased FOXP3 gene expression and the CD25+ CD4+ subpopulation of T cells but also a decrease in CD80 and CD86 expression. Lymphocyte (T and B cell) proliferation in response to myosin stimulation was significantly inhibited by CD40 silencing.CD40-siRNA is a useful tool for inhibiting in vivo CD40 expression, and it could have therapeutic potential in the prevention and treatment of myocarditis in humans. (Int Heart J 2014; 55: 539-545) Key words: RNA interference, Lymphocyte M yocarditis, an inflammatory heart muscle disease associated with cardiac dysfunction, can be caused by many agents, such as viruses and drugs, and is a potentially lethal disease, which can cause sudden death. 1,2)The disease has acute and chronic phases. Patients with myocarditis may develop dilated cardiomyopathy, which represents the chronic phase of the disease that leads to heart failure. 3)While there is still no effective therapy for myocarditis, recent studies have shown that autoimmunity plays an important role in the pathogenesis and development of myocarditis. 4) Experimental autoimmune myocarditis (EAM) is a model of post-infectious myocarditis, and can be induced by severe myocardial damage, including infiltration of mononuclear cells into the myocardium and activation of dendritic cells (DCs), with the subsequent activation of autoreactive T-cells, along with the secreted cytokines. 5-7)RNA interference is a post-transcriptional mechanism of gene silencing in which siRNA can lead to specific endonucleolytic cleavage of mRNA.8) RNA interference with siRNA is a specific, long-lasting, and straightforward approach for blocking the expression of specific genes.9) The therapeutic use of siRNA is promising, due to sequence-specific gene silencing, and has been successfully used in several animal models of diseases and clinical trials. 10)CD40 is a member of the TNF receptor superfamily and, as a co-stimulatory molecule, it plays critical roles in T cell activation and differentiation.11,12) CD40 expression can stimulate Th1 activation, 13,14) and the CD40/CD40 ligand (CD40L) interaction has been demonstrated to e...

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Novel Vaccination for Allergy through Gene Silencing of CD40 Using Small Interfering RNA

Cited by 30 publications

References 50 publications

Treatment of Autoimmune Arthritis Using RNA Interference-Modulated Dendritic Cells

Treatment of Autoimmune Arthritis Using RNA Interference-Modulated Dendritic Cells

Experience with lentivirus-mediated CD40 gene silencing in a mouse model of Graves' disease

Attenuation of Experimental Autoimmune Myocarditis by si-RNA Mediated CD40 Silencing

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