Adenovirus-induced maturation of dendritic cells through a PI3 kinase-mediated TNF-α induction pathway

Philpott, Nicola J.; Nociari, Marcelo; Elkon, Keith B.; Falck-Pedersen, Erik

doi:10.1073/pnas.0308368101

Cited by 105 publications

(98 citation statements)

References 47 publications

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“…The innate immune receptor to the Ad has not yet been identified. It has not even been determined whether TLRs are involved in Ad-mediated innate immune response in vivo, although it has been reported that TLR signals are not involved in the DC maturation induced by the Ad vector (46). As shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Increased cytokine/chemokine production after the injection of Ad vectors has been reported to be due to the introduction of input Ad vectors to Kupffer cells in the liver and DC (15,17,(43)(44)(45)(46). Detailed analysis of the organs responsible for the expression of cytokines, chemokines, and IFNs by RT-PCR suggests that their production can mainly be attributed to spleen cells (especially splenic conventional DC), not liver cells (Figs.…”

Section: Discussionmentioning

confidence: 99%

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Fiber-Modified Adenovirus Vectors Decrease Liver Toxicity through Reduced IL-6 Production

Koizumi

Yamaguchi

Kono

et al. 2007

The Journal of Immunology

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Adenovirus (Ad) vectors are one of the most commonly used viral vectors in gene therapy clinical trials. However, they elicit a robust innate immune response and inflammatory responses. Improvement of the therapeutic index of Ad vector gene therapy requires elucidation of the mechanism of Ad vector-induced inflammation and cytokine/chemokine production as well as development of the safer vector. In the present study, we found that the fiber-modified Ad vector containing poly-lysine peptides in the fiber knob showed much lower serum IL-6 and aspartate aminotransferase levels (as a maker of liver toxicity) than the conventional Ad vector after i.v. administration, although the modified Ad vector showed higher transgene production in the liver than the conventional Ad vector. RT-PCR analysis showed that spleen, not liver, is the major site of cytokine, chemokine, and IFN expression. Splenic CD11c+ cells were found to secret cytokines. The tissue distribution of Ad vector DNA showed that spleen distribution was much reduced in this modified Ad vector, reflecting reduced IL-6 levels in serum. Liver toxicity by the conventional Ad vector was reduced by anti-IL-6R Ab, suggesting that IL-6 signaling is involved in liver toxicity and that decreased liver toxicity of the modified Ad vector was due in part to the reduced IL-6 production. This study contributes to an understanding of the biological mechanism in innate immune host responses and liver toxicity toward systemically administered Ad vectors and will help in designing safer gene therapy methods that can reduce robust innate immunity and inflammatory responses.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Fiber-Modified Adenovirus Vectors Decrease Liver Toxicity through Reduced IL-6 Production

Koizumi

Yamaguchi

Kono

et al. 2007

The Journal of Immunology

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“…All TLRs are capable of signaling through the adaptor molecule MyD88, which has been shown to be nonessential for AdHu5 vector-induced DC maturation (17). Some TLRs, such as TLR3 and TLR4, can also signal independently of MyD88 (18).…”

Section: Ad-induced Type I Ifn Does Not Require Viral Transcription mentioning

confidence: 99%

“…Ad vectors efficiently transduce and express transgene in DCs (10 -12); however, viral gene expression is not necessary for Ad-mediated DC maturation (12)(13)(14). Although capsid components of Ad vectors are thought to trigger DC maturation, the exact viral proteins involved remain controversial (15)(16)(17).…”

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confidence: 99%

Dendritic Cell Maturation, but Not CD8+ T Cell Induction, Is Dependent on Type I IFN Signaling during Vaccination with Adenovirus Vectors

Hensley

Giles-Davis

McCoy

et al. 2005

The Journal of Immunology

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To understand how vaccines initiate adaptive immune responses, it is necessary to study how they interact with APCs such as dendritic cells (DCs). In this study, we analyzed interactions between recombinant adenovirus (Ad) vectors and mouse DCs. Mouse bone marrow-derived DCs transduced with Ad vectors produced type I IFN, which promoted the maturation of both transduced and bystander DCs. DCs transduced with a vector derived from a chimpanzee Ad serotype (AdC68) produced more type I IFN and matured more efficiently compared with DCs transduced with a vector derived from a human Ad serotype (AdHu5). Both vectors stimulated type I IFN production independently of viral transcription, replication, and TLR signaling. However, each vector induced type I IFN through distinct pathways; whereas AdHu5 vectors required phosphoinositide-3-OH kinase for type I IFN induction, AdC68 vectors did not. Both vectors induced strong transgene product-specific CD8+ T cell responses in wild-type mice. DCs isolated from mice that have a defect in type I IFN signaling failed to undergo full maturation after Ad vaccination, but surprisingly, these mice mounted strong transgene product-specific CD8+ T cell responses. In these mice, we were able to detect a small number of transduced DCs that expressed high levels of costimulatory molecules, and these DCs were able to stimulate transgene product-specific CD8+ T cells. Thus, type I IFN signaling is an important component of Ad-mediated DC maturation but is dispensable during the generation of transgene product-specific CD8+ T cell responses.

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“…These studies implicated the involvement of the TLR pathogen recognition system in Ad innate immune responses. While a previous study had suggested a lack of MyD88 (a critical TLR adaptor gene) dependence in the Ad-induced upregulation of CD86 in mouse dendritic cells in vitro (35), a different in vivo study found a reduction in Ad-elicited cytokines using an Ad challenge model in TLR4-deficient mice (40). Based upon these considerations we sought to further validate the transcriptome results in general through investigation of a critical TLR system adaptor gene, MyD88.…”

mentioning

confidence: 99%

Adenovirus Infection Triggers a Rapid, MyD88-Regulated Transcriptome Response Critical to Acute-Phase and Adaptive Immune Responses In Vivo

Hartman¹,

Kiang²,

Everett³

et al. 2007

J Virol

132

156

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Nearly 50 years ago, the discovery of interferon prompted the notion that host cells innately respond to viral invasion. Since that time, technological advances have allowed this response to be extensively characterized and dissected in vitro. However, these advances have only recently been applied to highly complex, in vivo biological systems. To this end, we exploited high-titer adenovirus (Ad) vectors to globally investigate the innate immune response to nonenveloped viral infection in vivo. Our results indicated a potent cellular transcriptome response shortly after infection, with global assessments revealing significant dysregulation in ϳ15% of the measured transcripts derived from Ad vector-transduced tissue. Bioinformatics-based transcriptome analysis revealed a complex innate response to Ad infection, with induction of proinflammatory responses (and suppression of metabolism and mitochondrial genes) akin to those observed when mice are challenged with lipopolysaccharide. Despite this commonality, there were many unique aspects of the Ad-dependent transcriptome response, including the upregulation of several RNA regulatory mechanisms and apoptosisrelated pathways, accompanied by the suppression of lysosomal and endocytic genes. Our results also implicated the Toll-like receptors (TLRs) in these responses, prompting specific investigations into this pathway. By using MyD88KO mice, our results confirmed that Ad-induced dysregulation of five functionally related gene clusters are significantly dependent on this TLR adaptor gene. MyD88 deficiency also resulted in significantly diminished, although not abolished, adaptive and acute-phase immune responses to Ad, confirming the transcriptome data, as well as specifically identifying MyD88 as a significant Ad immunity amplifier and regulator in vivo.For the past 100 years, a significant body of research has sought to understand the mammalian innate immune system, with recent efforts focusing on understanding its molecular workings (5). The discovery of a new family of "pathogen-sensing" genes, the Toll-like receptors (TLRs) and the deciphering of their role in mammalian innate immunity has been an especially robust area of recent investigation (2, 28). However, critical issues remain unanswered, chief among which is the intracellular innate response to viral infections in vivo. While recent studies have sought to investigate intracellular viral immunity and TLR involvement, almost all have relied on tissue culture systems, with little or no attention paid to in vivo models.

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Adenovirus-induced maturation of dendritic cells through a PI3 kinase-mediated TNF-α induction pathway

Cited by 105 publications

References 47 publications

Fiber-Modified Adenovirus Vectors Decrease Liver Toxicity through Reduced IL-6 Production

Fiber-Modified Adenovirus Vectors Decrease Liver Toxicity through Reduced IL-6 Production

Dendritic Cell Maturation, but Not CD8+ T Cell Induction, Is Dependent on Type I IFN Signaling during Vaccination with Adenovirus Vectors

Adenovirus Infection Triggers a Rapid, MyD88-Regulated Transcriptome Response Critical to Acute-Phase and Adaptive Immune Responses In Vivo

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