Double‐stranded secondary structures on mRNA induce type I interferon (IFN α/β) production and maturation of mRNA‐transfected monocyte‐derived dendritic cells

Ceppi, Maurizio; Ruggli, Nicolas; Tâche, Valérie; Gerber, Heidi; McCullough, Kenneth C.; Summerfield, Artur

doi:10.1002/jgm.685

Cited by 39 publications

(45 citation statements)

References 47 publications

(64 reference statements)

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“…As previously noticed, the discrepancy between our data that revealed maturation and activation of cDC, and results from previous in vitro studies indicating that CSFV-infected mo-DC did neither mature nor express any cytokine [13] was intriguing, whereas these in vitro-derived cells were able to produce TNF-α or IFN-α after mRNA transfection [15]. Other in vitro investigations showed that CSFV also disrupted secretion of IFN-α and proinflammatory cytokines in porcine aortic and kidney endothelial cell lines [7,11].…”

Section: Discussioncontrasting

confidence: 97%

“…This observation was in agreement with in vitro studies showing that mo-DC functionalities were more affected than NIPC by CSFV infection [4,13]. DC maturation after viral stimulation, demonstrated by down-regulation of CD1a expression and up-regulation of CD80/86 expression [12,15,31], was observed in both DC types. Less cDC expressed CD1a in tonsil and blood early after inoculation, and cDC maturation was clearly evidenced in blood through CD80/86 up-regulation.…”

Section: Discussionsupporting

confidence: 91%

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Classical swine fever virus induces activation of plasmacytoid and conventional dendritic cells in tonsil, blood, and spleen of infected pigs

et al. 2007

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-Classical swine fever virus (CSFV) compromises the host immune system, causing indirect leucopoenia and disruption of in vitro T cell stimulation capacity. In order to explore the potential role of dendritic cells (DC) in such phenomena, the activation of conventional DC (cDC) and plasmacytoid DC (pDC) in blood and secondary lymphoid organs of infected pigs was investigated in the early time course post-inoculation (pi), together with viral components dissemination and cytokine production in serum. Whereas CD11R1 + CD172a + cDC frequencies were markedly reduced in blood and spleen, analysis of CD4 + CD172a + pDC numbers revealed a rapid turn-over of this DC subset in tissues pi. Both subsets matured and were activated after infection, as demonstrated by down-regulation of CD1a, up-regulation of the co-stimulation molecule CD80/86 and expression of cytokines. cDC essentially expressed tumor necrosis factor alpha (TNF-α) and interleukin (IL)-10, whereas pDC produced alpha interferon (IFN-α) and IL-12. IFN-α and TNF-α productions revealed an enhancement of innate anti-viral immune responses. Detection of antigen activated B lymphocytes in tonsil T-cell areas at 72 h pi, subsequently to the transient translocation of the viral E2 protein within germinal centres at 48 h pi, indicates the initiation of humoral response. This response was also evidenced by an important IL-10 production in serum one week pi. IL-12 expression in organs, as well as transient detection of IL-18 and IFN-γ in serum, reflected the initiation of cellular immune responses. However, the uncommonly high levels of TNF-α and IFN-α produced by DC and measured in serum early post-infection, together with IL-10 expression in spleen, could play a role in the disruption of immune system cells, either inducing apoptosis or impairing DC functionalities themselves.antigen presenting cells / secondary lymphoid organs / interferon / E2 antigen / pestivirus

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Section: Discussioncontrasting

confidence: 97%

Section: Discussionsupporting

confidence: 91%

Classical swine fever virus induces activation of plasmacytoid and conventional dendritic cells in tonsil, blood, and spleen of infected pigs

et al. 2007

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“…28 We cannot exclude the possibility of immune system activation by the primary and secondary structures of mRNA via TLR3, TLR7 and TLR8 Toll-like receptors of DCs. [40][41][42][43][44][45][46] Similar contribution from MART1 mRNA lipopolyplexes could be explored using gene-deficient mice. In our system, the effect of MART1 mRNA immunization was much higher than of MART1 DNA immunization because DNA transfection of APC requires the plasmid import in the nucleus.…”

Section: Discussionmentioning

confidence: 99%

mRNA-based cancer vaccine: prevention of B16 melanoma progression and metastasis by systemic injection of MART1 mRNA histidylated lipopolyplexes

et al. 2007

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Immunization with mRNA encoding tumor antigen is an emerging vaccine strategy for cancer. In this paper, we demonstrate that mice receiving systemic injections of MART1 mRNA histidylated lipopolyplexes were specifically and significantly protected against B16F10 melanoma tumor progression. The originality of this work concerns the use of a new tumor antigen mRNA formulation as vaccine, which allows an efficient protection against the growth of a highly aggressive tumor model after its delivery by intravenous route. Synthetic melanoma-associated antigen MART1 mRNA was formulated with a polyethylene glycol (PEG)ylated derivative of histidylated polylysine and L-histidine-(N,N-di-n-hexadecylamine)ethylamide liposomes (termed histidylated lipopolyplexes). Lipopolyplexes comprised mRNA/polymer complexes encapsulated by liposomes. The tumor protective effect was induced with MART1 mRNA carrying a poly(A) tail length of 100 adenosines at an optimal dose of 12.5 mg per mouse. MART1 mRNA lipopolyplexes elicited a cellular immune response characterized by the production of interferon-g and the induction of cytotoxic T lymphocytes. Finally, the anti-B16 response was enhanced using a formulation containing both MART1 mRNA and MART1-LAMP1 mRNA encoding the antigen targeted to the major histocompatibility complex class II compartments by the lysosomal sorting signal of LAMP1 protein. Our results provide a basis for the development of mRNA histidylated lipopolyplexes for cancer vaccine.

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“…Nucleic acid may be internalized by DC, but this is not regarded as particularly efficient [88]. Delivery of 'naked' RNA is a rare event in the scientific literature, which is dominated by employment of delivery vehicles for both prophylactic [38,60,64,87,89,90] and therapeutic [59,84,87,90] applications.…”

Section: Rna Delivery To Dcsmentioning

confidence: 99%

Functional RNA Delivery Targeted to Dendritic Cells By Synthetic Nanoparticles

McCullough¹,

Bassi²,

Démoulins³

et al. 2012

Therapeutic Delivery

102

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ReviewTargeting the immune system Dendritic cells (DCs) play crucial roles in promoting and regulating immune defenses, providing important targets for prophylactic and therapeutic approaches (FiguRe 1). Particulate formulations, including liposomes and other nanoparticles, have been employed as delivery vehicles. Despite the large number of reports, current in-depth knowledge on the cellular processes involved remains relatively limited, particularly for nucleic acid delivery. Certain structures in the nucleic acid may also signal the cell in the sense of an adjuvant or immunomodulatory activity. Importantly, the optimized characteristics for delivery of an antigen or therapeutic agent may be distinct from those for nucleic acid delivery, especially RNA species. Moreover, RNA delivery for interference therapy will not necessarily require the same delivery routes as mRNA delivery wherein RNA translation is the main requisite.The efficacy of delivery can be further improved by targeting the appropriate cells of the immune system, an area in which nanoparticle-based delivery platforms have found an important niche [1]. Advances with prophylactic applications can also prove valuable for therapeutic applications and vice versa, as seen with RNA delivery. This review will consider how growing knowledge on delivery mechanisms has found application with nucleic acids, in both prophylaxis and therapy, focusing on interaction with DCs.The initial components of the DC endocytic pathways are critically important in determining how the cell handles the delivered material; thereafter, correct cytosolic delivery is a critical element for a number of desired outcomes, including delivery of nucleic acids. Advances made with protein delivery -in particular, vaccines -are of value to highlight the potential of a particular mode of application or the high risk for nucleic acid integrity. Particularly pertinent is the application of cationic elements in the delivery mechanisms and how application of ligands for cell receptors influence intracellular compartmentalization.It is not the aim of the present review to retrace all the fine details of work contributing to our current knowledge. Accordingly, review articles covering areas that have already received considerable attention will be employed and assimilated to provide a more elaborate picture of the current situation. This will allow a focusing on more recent advances, along with problems and pitfalls therein. While advances on protein and DNA delivery will be presented, these will be used to highlight how our current knowledge can be applied to RNA delivery. There are numerous reviews on protein delivery to DC, wherein many of the procedures employed are not relevant for RNA delivery, which must escape into the cytosol undamaged. With DNA delivery, there is also the question of whether the DNA will activate the DC or reach the nucleus for transcription; this latter area has most often Functional RNA delivery targeted to dendritic cells by synthetic nanoparticles Dendritic cell...

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Double‐stranded secondary structures on mRNA induce type I interferon (IFN α/β) production and maturation of mRNA‐transfected monocyte‐derived dendritic cells

Cited by 39 publications

References 47 publications

Classical swine fever virus induces activation of plasmacytoid and conventional dendritic cells in tonsil, blood, and spleen of infected pigs

Classical swine fever virus induces activation of plasmacytoid and conventional dendritic cells in tonsil, blood, and spleen of infected pigs

mRNA-based cancer vaccine: prevention of B16 melanoma progression and metastasis by systemic injection of MART1 mRNA histidylated lipopolyplexes

Functional RNA Delivery Targeted to Dendritic Cells By Synthetic Nanoparticles

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