Poxvirus as a vector to transduce human dendritic cells for immunotherapy: abortive infection but reduced APC function

Jenne, Lars; Hauser, Conrad; Arrighi, J-F; Jh, Saurat; Aw, Hügin

doi:10.1038/sj.gt.3301287

Cited by 105 publications

(93 citation statements)

References 67 publications

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“…Yet, studies on infected DC exhibited that VV was a potent inhibitor of DC maturation and severely reduced the ability of DC to induce proliferation of naïve T cells, typically one of the hallmarks of the mature DC. We and other groups also found that VV reduces the expression of CD80 and CD83 on mature DC, and, in case of CD80, also in uninfected bystander DC [30][31][32].…”

Section: Introductionsupporting

confidence: 67%

“…Collectively, these viral interactions, which apparently function to keep the infected DC trapped to the site of VV activity, and consequently to inhibit an anti-viral immune response, lead to an intercellular communication breakdown and paralysis of professional APC. Apart from this, and in addition to recent results referring to reduced allostimulatory capacity and down-regulation of costimulatory molecules of VV-infected DC [30,31], the results of this study contribute to doubts whether WR and MVA in their current forms are suitable expression vectors for DC-based immunotherapy.…”

Section: Discussionsupporting

confidence: 52%

“…However, recent analysis of VV-infected DC have revealed several new viral mechanisms that perturb important functions of DC [30][31][32]. In this study, we have shown for the first time that infection with VV results in an abrogation of directional migration of mature DC toward the lymphoid chemokines CCL19 and CXCL12, fundamental for the induction of adaptive immunity.…”

Section: Discussionmentioning

confidence: 67%

“…Recent analysis of VV-infected DC have revealed several new viral mechanisms that perturb important functions of DC [29]. Accordingly, it was shown that even though VV effectively infects DC, only viral genes regulated by early and (though to a far lesser degree) early intermediate genes were expressed in monocyte-derived DC, and thus no viral replication occurs in human DC [30]. Yet, studies on infected DC exhibited that VV was a potent inhibitor of DC maturation and severely reduced the ability of DC to induce proliferation of naïve T cells, typically one of the hallmarks of the mature DC.…”

Section: Introductionmentioning

confidence: 99%

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Vaccinia virus impairs directional migration and chemokine receptor switch of human dendritic cells

Humrich¹,

Thumann²,

Greiner³

et al. 2007

Eur J Immunol

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A crucial event for the induction of an anti-viral immune response is the coordinated, phenotype-dependent migration of dendritic cells (DC) to sites of infection and secondary lymphoid organs. Here we show that the vaccinia virus (VV) strains Western Reserve (WR) and modified virus Ankara (MVA) inhibit directional migration of mature DC toward the lymphoid chemokines CCL19 and CXCL12 without affecting surface expression of the respective chemokine receptors or impairing undirected cellular locomotion. Instead, infection with VV results in a deficiency of extracellular signalregulated kinase-1 and a disturbance of intracellular calcium mobilization, indicating a viral interference with signaling events downstream of the surface chemokine receptors. In immature DC, apart from inhibiting chemokine-induced migration of infected DC, infection with both VV strains increases expression of the inflammatory chemokine receptors CCR1 and CXCR1 on non-infected bystander DC, which depends on the activity of IFN-a. Although functional, these chemokine receptors are resistant to lipopolysaccharide-induced down-regulation. In addition, VV-infected and noninfected bystander DC fail to up-regulate the lymphoid chemokine receptor CCR7 upon activation, together pointing to a disability to undergo the chemokine receptor switch. This study shows that VV targets directional migration of professional antigenpresenting cells at multiple functional levels, revealing a potent viral strategy of immune escape.See accompanying commentary: http://dx

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Section: Introductionsupporting

confidence: 67%

Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Vaccinia virus impairs directional migration and chemokine receptor switch of human dendritic cells

Humrich¹,

Thumann²,

Greiner³

et al. 2007

Eur J Immunol

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“…However, plasmid DNA transfer into DC has not been very efficient (17), and the use of viral vectors for transduction of DC implies a more complex and laborious manipulation associated with safety issues. Moreover, DC transduced by viral vectors have been reported to have impaired function in terms of stimulatory capacity (18,19). Recently, we (20) and others (21-23) developed novel non-viral Ag loading technologies based on the passive pulsing, lipofection, and electroporation of mRNA.…”

mentioning

confidence: 99%

Messenger RNA Electroporation of Human Monocytes, Followed by Rapid In Vitro Differentiation, Leads to Highly Stimulatory Antigen-Loaded Mature Dendritic Cells

Ponsaerts

Bosch

Cools

et al. 2002

The Journal of Immunology

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Dendritic cells (DC) are professional Ag-capturing and -presenting cells of the immune system. Because of their exceptional capability of activating tumor-specific T cells, cancer vaccination research is now shifting toward the formulation of a clinical human DC vaccine. We developed a short term and serum-free culture protocol for rapid generation of fully mature, viable, and highly stimulatory CD83+ DC. Human monocytes were cultured for 24 h in serum-free AIM-V medium, followed by 24-h maturation by polyriboinosinic polyribocytidylic acid (polyI:C). Short term cultured, polyI:C-maturated DC, far more than immature DC, showed typical mature DC markers and high allogeneic stimulatory capacity and had high autologous stimulatory capacity in an influenza model system using peptide-pulsed DC. Electroporation of mRNA as an Ag-loading strategy in these cells was optimized using mRNA encoding the enhanced green fluorescent protein (EGFP). Monocytes electroporated with EGFP mRNA, followed by short term, serum-free differentiation to mature DC, had a phenotype of DC, and all showed positive EGFP fluorescence. Influenza matrix protein mRNA-electroporated monocytes cultured serum-free and maturated with polyI:C showed high stimulatory capacity in autologous T cell activation experiments. In conclusion, the present short term and serum-free ex vivo DC culture protocol in combination with mRNA electroporation at the monocyte stage imply an important reduction in time and consumables for preparation of Ag-loaded mature DC compared with classical DC culture protocols and might find application in clinical immunotherapy settings.

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Efficiency of cross presentation of vaccinia virus-derived antigens by human dendritic cells

et al. 2001

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Dendritic cells (DC) utilize at least two pathways to process viral antigens onto MHC class I molecules. The conventional endogenous route is used to acquire antigens from both infectious and non‐replicating virions. Exogenous pathways are used by DC to acquire and "cross‐present" antigens derived from virus‐infected donor cells that by themselves lack the ability to activate T cells directly. We analyzed the role of this pathway for antigens derived from vaccinia, a virus which inhibits DC maturation and causes extensive apoptosis of infected cells, yet is highly immunogenic. Using recombinant vaccinia virus encoding the influenza matrix protein as model vector, DC were shown to cross‐present vaccinia‐derived antigens from both apoptotic and necrotic infected cells to antigen‐specific CD8+ T cells. Efficient cross presentation required uptake of dead cells by immature DC and exposure to maturation stimuli, especially CD40 ligand. The responding CD8+ Tcells secreted IL‐2 and IFN‐γ, proliferated and developed into cytotoxic effectors. Quantification of the cross presentation of vaccinia‐derived antigens showed this pathway to be highly efficient, corresponding to a peptide pulse of 10–100 nM. While monocytes also phagocytosed apoptotic and necrotic cells, they were far less efficient at cross‐presenting vaccinia‐derived antigens to CD8+ T cells. The ability of DC to cross‐present vaccinia‐derived antigens from infected apoptotic cells or necrotic cell lysates, bypasses the deleterious effects of direct infection of DC and provides one explanation for this pathogen's immunogenicity.

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Poxvirus as a vector to transduce human dendritic cells for immunotherapy: abortive infection but reduced APC function

Cited by 105 publications

References 67 publications

Vaccinia virus impairs directional migration and chemokine receptor switch of human dendritic cells

Vaccinia virus impairs directional migration and chemokine receptor switch of human dendritic cells

Messenger RNA Electroporation of Human Monocytes, Followed by Rapid In Vitro Differentiation, Leads to Highly Stimulatory Antigen-Loaded Mature Dendritic Cells

Efficiency of cross presentation of vaccinia virus-derived antigens by human dendritic cells

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