Regulation of human dendritic cells by a novel specific nuclear factor–κB inhibitor, dehydroxymethylepoxyquinomicin

Shinoda, Kazunobu; Nakagawa, Ken; Kosaka, Takeo; Tanaka, Nobuyuki; Maeda, Takahiro; Kono, Hidaka; Mizuno, Ryuichi; Kikuchi, Eiji; Miyajima, Akira; Umezawa, Kazuo; Oya, Mototsugu

doi:10.1016/j.humimm.2010.05.009

Cited by 12 publications

(14 citation statements)

References 30 publications

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“…Expression of CS protein by the parasite may have evolved to counteract this inflammatory response and prevent excessive induction of malaria specific adaptive immune responses in the infected host. Interestingly, recent studies on an immunosuppressive drug (dehydroxymethylepoxyquinomicin) that specifically interferes with the NF-κB-importan α interaction was shown at lower doses to only modestly affect IL-6 and TNFα levels, while dramatically affecting T h 1 expansion, results paralleling those noted in our experiments [45].…”

Section: Discussionsupporting

confidence: 90%

Vaccine Platforms Combining Circumsporozoite Protein and Potent Immune Modulators, rEA or EAT-2, Paradoxically Result in Opposing Immune Responses

et al. 2011

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BackgroundMalaria greatly impacts the health and wellbeing of over half of the world's population. Promising malaria vaccine candidates have attempted to induce adaptive immune responses to Circumsporozoite (CS) protein. Despite the inclusion of potent adjuvants, these vaccines have limited protective efficacy. Conventional recombinant adenovirus (rAd) based vaccines expressing CS protein can induce CS protein specific immune responses, but these are essentially equivalent to those generated after use of the CS protein subunit based vaccines. In this study we combined the use of rAds expressing CS protein along with rAds expressing novel innate immune response modulating proteins in an attempt to significantly improve the induction of CS protein specific cell mediated immune (CMI) responses.Methods and FindingsBALB/cJ mice were co-vaccinated with a rAd vectors expressing CS protein simultaneous with a rAd expressing either TLR agonist (rEA) or SLAM receptors adaptor protein (EAT-2). Paradoxically, expression of the TLR agonist uncovered a potent immunosuppressive activity inherent to the combined expression of the CS protein and rEA. Fortunately, use of the rAd vaccine expressing EAT-2 circumvented CS protein's suppressive activity, and generated a fivefold increase in the number of CS protein responsive, IFNγ secreting splenocytes, as well as increased the breadth of T cells responsive to peptides present in the CS protein. These improvements were positively correlated with the induction of a fourfold improvement in CS protein specific CTL functional activity in vivo.ConclusionOur results emphasize the need for caution when incorporating CS protein into malaria vaccine platforms expressing or containing other immunostimulatory compounds, as the immunological outcomes may be unanticipated and/or counter-productive. However, expressing the SLAM receptors derived signaling adaptor EAT-2 at the same time of vaccination with CS protein can overcome these concerns, as well as significantly improve the induction of malaria antigen specific adaptive immune responses in vivo.

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Section: Discussionsupporting

confidence: 90%

Vaccine Platforms Combining Circumsporozoite Protein and Potent Immune Modulators, rEA or EAT-2, Paradoxically Result in Opposing Immune Responses

et al. 2011

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“…3 and 4 and in reference 22 using a dNS1 mutant virus. The production of the proinflammatory cytokines TNF-␣ and IL-6, characteristic of DC activation, is driven by the activation of the NF-〉 transcription factors (33,(37)(38)(39). Also, it is known that type I IFN induces NF-〉 activation (reviewed in references 31 and 40), so it is possible that the induction of TNF-␣ and IL-6 observed in dNS1 PR8-infected cells is mainly due to IFN secretion in those infected cells that in turn promotes activation of NF-〉.…”

Section: Resultsmentioning

confidence: 99%

Contribution of Double-Stranded RNA and CPSF30 Binding Domains of Influenza Virus NS1 to the Inhibition of Type I Interferon Production and Activation of Human Dendritic Cells

Ramos

Carnero

Bernal-Rubio

et al. 2013

J Virol

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“…Non‐specific binding of dextran to DCs was determined by incubating DCs with FITC‐conjugated dextran at 4°C. This value was subtracted to determine the levels of specific binding, as described previously [32].…”

Section: Methodsmentioning

confidence: 99%

Stimulation of dendritic cells withHelicobacter pylorivacuolating cytotoxin negatively regulates their maturation via the restoration of E2F1

Kim

Yoo

et al. 2011

Clinical and Experimental Immunology

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Regulation of human dendritic cells by a novel specific nuclear factor–κB inhibitor, dehydroxymethylepoxyquinomicin

Cited by 12 publications

References 30 publications

Vaccine Platforms Combining Circumsporozoite Protein and Potent Immune Modulators, rEA or EAT-2, Paradoxically Result in Opposing Immune Responses

Vaccine Platforms Combining Circumsporozoite Protein and Potent Immune Modulators, rEA or EAT-2, Paradoxically Result in Opposing Immune Responses

Contribution of Double-Stranded RNA and CPSF30 Binding Domains of Influenza Virus NS1 to the Inhibition of Type I Interferon Production and Activation of Human Dendritic Cells

Stimulation of dendritic cells withHelicobacter pylorivacuolating cytotoxin negatively regulates their maturation via the restoration of E2F1

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