FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2086651005> ?p ?o ?g. }

• W2086651005 endingPage "696" @default.
• W2086651005 startingPage "685" @default.
• W2086651005 abstract "More than 300 human clinical trials utilize recombinant adenoviruses (rAds) as a gene transfer vector, confirming that rAds continue to be of high clinical interest. A primary weakness of rAds is their known propensity to trigger an innate, proinflammatory immune response rapidly after high-dose, systemic administration. In this study, we investigated what affects that pre-emptive treatment with anti-inflammatory glucocorticoids might have upon Ad vector-triggered inflammatory immune responses. We found that a simple pretreatment regimen with Dexamethasone (DEX) can significantly reduce most Ad-induced innate immune responses. DEX prevented rAd induction of systemic cytokine/chemokine releases in a dose-dependent fashion, with higher dosages preventing rAd induction of acute thrombocytopenia, endothelial cell activation, proinflammatory gene induction, and leukocyte infiltration into transduced organs. Transient glucocorticoid pretreatment also significantly reduced rAd-induced adaptive immune responses, including a decreased induction of Ad-neutralizing antibodies (NAbs). Importantly, use of DEX did not reduce the efficacy of rAd-mediated gene transduction nor rAd-derived transgene expression. Our results demonstrate that a simple, pre-emptive and transient glucocorticoid pretreatment is a viable approach to reduce rAd-associated acute toxicities that currently limit the use of Ad vectors in systemic clinical applications. More than 300 human clinical trials utilize recombinant adenoviruses (rAds) as a gene transfer vector, confirming that rAds continue to be of high clinical interest. A primary weakness of rAds is their known propensity to trigger an innate, proinflammatory immune response rapidly after high-dose, systemic administration. In this study, we investigated what affects that pre-emptive treatment with anti-inflammatory glucocorticoids might have upon Ad vector-triggered inflammatory immune responses. We found that a simple pretreatment regimen with Dexamethasone (DEX) can significantly reduce most Ad-induced innate immune responses. DEX prevented rAd induction of systemic cytokine/chemokine releases in a dose-dependent fashion, with higher dosages preventing rAd induction of acute thrombocytopenia, endothelial cell activation, proinflammatory gene induction, and leukocyte infiltration into transduced organs. Transient glucocorticoid pretreatment also significantly reduced rAd-induced adaptive immune responses, including a decreased induction of Ad-neutralizing antibodies (NAbs). Importantly, use of DEX did not reduce the efficacy of rAd-mediated gene transduction nor rAd-derived transgene expression. Our results demonstrate that a simple, pre-emptive and transient glucocorticoid pretreatment is a viable approach to reduce rAd-associated acute toxicities that currently limit the use of Ad vectors in systemic clinical applications. IntroductionAdenovirus (Ad)-based vectors continue to be the most commonly utilized gene transfer vector in a variety of potential applications. Ad vectors can be easily produced to high titers (scalability is a critical point when considering potential human applications) possess the ability to transduce dividing and nondividing cells without the need for chromosomal integration and have an extremely broad tropism. These advantages have resulted in the initiation of 342 human clinical trials utilizing Ad vectors since the first Ad clinical trial in 1993 (http://www.wiley.co.uk/wileychi/genmed/clinical/). Furthermore, first-generation Ad vectors have been repeatedly demonstrated to persist for long periods when transducing nonimmunogenic transgenes.1Maelandsmo GM Ross PJ Pavliv M Meulenbroek RA Evelegh C Muruve DA et al.Use of a murine secreted alkaline phosphatase as a non-immunogenic reporter gene in mice.J Gene Med. 2005; 7: 307-315Crossref PubMed Scopus (24) Google Scholar Limitations to long-term persistence of first-generation Ads-transducing immunogenic transgenes have been largely overcome with the development of multiply deleted, helper-independent, or fully deleted helper virus-dependent, advanced-generation, Ad-based vectoring systems.2Amalfitano A Parks RJ Separating fact from fiction: assessing the potential of modified adenovirus vectors for use in human gene therapy.Curr Gene Ther. 2002; 2: 111-133Crossref PubMed Scopus (122) Google Scholar Despite these encouraging facts, safety concerns regarding Ad vector-associated innate toxicities, responses that often prime subsequent adaptive immune responses, have severely limited progress in the use of this important vector class for systemic applications, such as gene transfer to the liver.Several approaches have been studied to minimize the inflammatory responses acutely induced by systemic exposure to Ad vectors. These approaches include genetic modification of the Ad capsid to alter the tropism of the vector for liver cells, pre-emptive depletion (or blockade) of Ad sequestration by liver macrophages to minimize induction of macrophage-dependent inflammatory responses, use of immunosuppressive drugs (such as tumor necrosis factor blockers, Toll-like receptor 9 (TLR-9) inhibitors, extracellular signal-regulated kinase inhibitors, and others) to transiently block acute inflammatory responses, as well surgical isolation procedures to minimize systemic distribution of recombinant Ads (rAds).3Stone D Liu Y Li ZY Tuve S Strauss R Lieber A Comparison of adenoviruses from species B, C, E, and F after intravenous delivery.Mol Ther. 2007; 15: 2146-2153Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar,4Appledorn DM Kiang A McBride A Jiang H Seregin S Scott JM et al.Wild-type adenoviruses from groups A-F evoke unique innate immune responses, of which HAd3 and SAd23 are partially complement dependent.Gene Ther. 2008; 15: 885-901Crossref PubMed Scopus (47) Google Scholar,5Hartman ZC Appledorn DM Serra D Glass O Mendelson TB Clay TM et al.Replication-attenuated Human Adenoviral Type 4 vectors elicit capsid dependent enhanced innate immune responses that are partially dependent upon interactions with the complement system.Virology. 2008; 374: 453-467Crossref PubMed Scopus (28) Google Scholar,6Kuriyama S Tominaga K Mitoro A Tsujinoue H Nakatani T Yamazaki M et al.Immunomodulation with FK506 around the time of intravenous re-administration of an adenoviral vector facilitates gene transfer into primed rat liver.Int J Cancer. 2000; 85: 839-844Crossref PubMed Scopus (24) Google Scholar,7Appledorn DM Patial S McBride A Godbehere S Van Rooijen N Parameswaran N et al.Adenovirus vector-induced innate inflammatory mediators, MAPK signaling, as well as adaptive immune responses are dependent upon both TLR2 and TLR9 in vivo.J Immunol. 2008; 181: 2134-2144Crossref PubMed Scopus (162) Google Scholar,8Cerullo V Seiler MP Mane V Brunetti-Pierri N Clarke C Bertin TK et al.Toll-like receptor 9 triggers an innate immune response to helper-dependent adenoviral vectors.Mol Ther. 2007; 15: 378-385Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar,9Brunetti-Pierri N Stapleton GE Palmer DJ Zuo Y Mane VP Finegold MJ et al.Pseudo-hydrodynamic delivery of helper-dependent adenoviral vectors into non-human primates for liver-directed gene therapy.Mol Ther. 2007; 15: 732-740Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar All of these approaches have an ability to reduce portions of the multifaceted Ad-induced innate immune response, but their ability to impact upon the full inflammatory response induced by rAds is either limited or has not been fully determined. Furthermore, many of these approaches have inherent problems as well. For example, nonspecific toxicities are noted with use of clodronated liposomes; Ad capsid changes may result in significantly altered tropisms and bio-distribution patterns that can correlate with an enhanced innate toxicity, and technical difficulties may be associated with moderate to significantly invasive surgical procedures.4Appledorn DM Kiang A McBride A Jiang H Seregin S Scott JM et al.Wild-type adenoviruses from groups A-F evoke unique innate immune responses, of which HAd3 and SAd23 are partially complement dependent.Gene Ther. 2008; 15: 885-901Crossref PubMed Scopus (47) Google Scholar,5Hartman ZC Appledorn DM Serra D Glass O Mendelson TB Clay TM et al.Replication-attenuated Human Adenoviral Type 4 vectors elicit capsid dependent enhanced innate immune responses that are partially dependent upon interactions with the complement system.Virology. 2008; 374: 453-467Crossref PubMed Scopus (28) Google Scholar,10Shayakhmetov DM Eberly AM Li ZY Lieber A Deletion of penton RGD motifs affects the efficiency of both the internalization and the endosome escape of viral particles containing adenovirus serotype 5 or 35 fiber knobs.J Virol. 2005; 79: 1053-1061Crossref PubMed Scopus (95) Google Scholar What is needed is a safe, simple, transient, inexpensive, and widely accepted method for the reduction and/or elimination of the myriad Ad vector-induced inflammatory responses induced after systemic administration.It is noteworthy that the synthetic anti-inflammatory glucocorticoid Dexamethasone (DEX) is an FDA-approved drug widely used to treat a number of transient and/or chronic inflammatory conditions.11Kardash KJ Sarrazin F Tessler MJ Velly AM Single-dose dexamethasone reduces dynamic pain after total hip arthroplasty.Anesth Analg. 2008; 106 (table of contents): 1253-1257Crossref PubMed Scopus (137) Google Scholar,12Pace TW Hu F Miller AH Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression.Brain Behav Immun. 2007; 21: 9-19Crossref PubMed Scopus (451) Google Scholar Importantly, mechanisms of action of DEX include preventing the activation of nuclear factor κB (NF-κB) and AP1 transcription factors, as well as mitogen-activated protein kinases, all of which have been shown by us and others to also be important mediators of the Ad-induced inflammatory response complex.13Mogensen TH Berg RS Paludan SR Ostergaard L Mechanisms of dexamethasone-mediated inhibition of Toll-like receptor signaling induced by Neisseria meningitidis and Streptococcus pneumoniae.Infect Immun. 2008; 76: 189-197Crossref PubMed Scopus (54) Google Scholar Interleukin (IL)-8 and interferon β production have also been shown to be inhibited by DEX.13Mogensen TH Berg RS Paludan SR Ostergaard L Mechanisms of dexamethasone-mediated inhibition of Toll-like receptor signaling induced by Neisseria meningitidis and Streptococcus pneumoniae.Infect Immun. 2008; 76: 189-197Crossref PubMed Scopus (54) Google Scholar As a result, the maturation of mast cell progenitors, as well as granulocyte–macrophage colony–stimulating factor and tumor necrosis factor-α secretion by mast cells, are also altered by DEX treatment.14Smith SJ Piliponsky AM Rosenhead F Elchalal U Nagler A Levi-Schaffer F Dexamethasone inhibits maturation, cytokine production and Fc epsilon RI expression of human cord blood-derived mast cells.Clin Exp Allergy. 2002; 32: 906-913Crossref PubMed Scopus (48) Google ScholarVery limited data are available regarding the effects that DEX treatment has on animals treated with gene transfer agents. Use of glucocorticoids has been shown to increase the efficacy of gene transfer in vitro; in vivo studies showed that DEX could improve nonviral gene and virus-derived gene expression in experimental animal models.15Braun S Jenny C Thioudellet C Perraud F Claudepierre MC Langle-Rouault F et al.In vitro and in vivo effects of glucocorticoids on gene transfer to skeletal muscle.FEBS Lett. 1999; 454: 277-282Abstract Full Text PDF PubMed Scopus (23) Google Scholar,16Liu Y Liggitt HD Dow S Handumrongkul C Heath TD Debs RJ Strain-based genetic differences regulate the efficiency of systemic gene delivery as well as expression.J Biol Chem. 2002; 277: 4966-4972Crossref PubMed Scopus (13) Google Scholar,17Ishimoto S Kawamoto K Stover T Kanzaki S Yamasoba T Raphael Y A glucocorticoid reduces adverse effects of adenovirus vectors in the cochlea.Audiol Neurootol. 2003; 8: 70-79Crossref PubMed Scopus (27) Google Scholar Relative to Ad-mediated gene transfer, DEX can improve Ad vector-derived gene expression when these vectors are directly administered into the spinal cord, nasal mucosa, inner ear, or lungs.17Ishimoto S Kawamoto K Stover T Kanzaki S Yamasoba T Raphael Y A glucocorticoid reduces adverse effects of adenovirus vectors in the cochlea.Audiol Neurootol. 2003; 8: 70-79Crossref PubMed Scopus (27) Google Scholar,18Otake K Ennist DL Harrod K Trapnell BC Nonspecific inflammation inhibits adenovirus-mediated pulmonary gene transfer and expression independent of specific acquired immune responses.Hum Gene Ther. 1998; 9: 2207-2222Crossref PubMed Scopus (142) Google Scholar,19Price AR Limberis MP Wilson JM Diamond SL Pulmonary delivery of adenovirus vector formulated with dexamethasone-spermine facilitates homologous vector re-administration.Gene Ther. 2007; 14: 1594-1604Crossref PubMed Scopus (23) Google Scholar Pulmonary delivery of Ad vectors into mice pretreated with DEX/spermine resulted in a reduced activation of limited portions of the lung-specific innate and adaptive immune response to the Ad vector utilized.19Price AR Limberis MP Wilson JM Diamond SL Pulmonary delivery of adenovirus vector formulated with dexamethasone-spermine facilitates homologous vector re-administration.Gene Ther. 2007; 14: 1594-1604Crossref PubMed Scopus (23) Google ScholarThese results prompted us to evaluate the efficacy of DEX to prevent the numerous innate toxicities induced by systemic administration of Ad vectors. In our study, we intravenously injected high doses of a first-generation (E1-deleted) Ad5 vector encoding a highly immunogenic transgene (Bacterial B-galactosidase (LacZ)) into either control or DEX pretreated C57BL/6 mice, and investigated the subsequent innate and adaptive immune responses to the Ad and the LacZ protein expressed by the vector. Our results demonstrate that multiple aspects of the systemic inflammatory response typically induced rapidly after systemic delivery of Ads can be minimized or obliterated by simple, transient pretreatment with a potent glucocorticoid, in a dose-dependent fashion.ResultsDEX blocks Ad-mediated cytokine and chemokine release in C57BL/6 mice in a dose-dependent mannerWe quantified the release of inflammatory cytokines and chemokines in murine plasma at 1 and 6 hours after systemic Ad delivery utilizing a multiplexed, bead array–based detection system. Based on our previous publications, as well those of others, we focused upon seven cytokines and chemokines that are known to be rapidly (within 1–6 hours) induced following systemic injection of Ad vectors.4Appledorn DM Kiang A McBride A Jiang H Seregin S Scott JM et al.Wild-type adenoviruses from groups A-F evoke unique innate immune responses, of which HAd3 and SAd23 are partially complement dependent.Gene Ther. 2008; 15: 885-901Crossref PubMed Scopus (47) Google Scholar,20Kiang A Hartman ZC Everett RS Serra D Jiang H Frank MM et al.Multiple innate inflammatory responses induced after systemic adenovirus vector delivery depend on a functional complement system.Mol Ther. 2006; 14: 588-598Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar Keratinocyte derived chemokine (chemokine (C–X–C motif) ligand 1) and monocyte chemoattractant protein 1 are the first inflammatory chemokines to be induced (within 1 hour of Ad injection). These murine chemokines are known to recruit neutrophils and monocytes to the sites of tissue damage, comprising one of the first defensive barriers to Ad vectors.4Appledorn DM Kiang A McBride A Jiang H Seregin S Scott JM et al.Wild-type adenoviruses from groups A-F evoke unique innate immune responses, of which HAd3 and SAd23 are partially complement dependent.Gene Ther. 2008; 15: 885-901Crossref PubMed Scopus (47) Google Scholar,20Kiang A Hartman ZC Everett RS Serra D Jiang H Frank MM et al.Multiple innate inflammatory responses induced after systemic adenovirus vector delivery depend on a functional complement system.Mol Ther. 2006; 14: 588-598Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar At 6 hpi, plasma levels of IL-6, IL-12p40, granulocyte colony–stimulating factor, macrophage inflammatory protein 1β, and normal T-cell Expressed and Secreted (RANTES) also reach a peak, further activating the cellular arm of the innate immune system.4Appledorn DM Kiang A McBride A Jiang H Seregin S Scott JM et al.Wild-type adenoviruses from groups A-F evoke unique innate immune responses, of which HAd3 and SAd23 are partially complement dependent.Gene Ther. 2008; 15: 885-901Crossref PubMed Scopus (47) Google Scholar,20Kiang A Hartman ZC Everett RS Serra D Jiang H Frank MM et al.Multiple innate inflammatory responses induced after systemic adenovirus vector delivery depend on a functional complement system.Mol Ther. 2006; 14: 588-598Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar As expected, these seven cytokines and chemokines were induced after Ad injection into wild-type (WT) mice (Figure 1). To investigate the impact of DEX pretreatment (15 hours and 2 hours prior to intravenous Ad5-LacZ injection) in the induction of these proinflammatory factors, we completed a dose–response study where mice were pretreated with 10 mg/kg, 1 mg/kg, or 0.1 mg/kg of DEX. At 1 hour postinjection of Ad5-LacZ, the level of keratinocyte derived chemokine in the serum of DEX pretreated mice (all dosages) was significantly lower compared to mice identically injected with Ad. RANTES levels at 6 hpi were also equivalently reduced by DEX. Interestingly, we did not observe a dose-dependent reduction of these chemokines, as the 0.1 mg/kg dose was as efficacious as the 10 mg/kg dose in modulating the induction of both keratinocyte derived chemokine and RANTES.At a dose of 10 mg/kg, DEX completely blocked the release of IL-6 and macrophage inflammatory protein 1β (P < 0.001) at 6 hpi, and monocyte chemoattractant protein 1 and IL-12(p40) at both 1 and 6 hpi (P < 0.001). The levels of IL-12(p40) and monocyte chemoattractant protein 1, at both time points, were also significantly reduced when mice were pretreated with either 1.0 or 0.1 mg/kg DEX. Serum levels of macrophage inflammatory protein 1β and IL-6 were also significantly lower in mice pretreated with 10.0 or 1 mg/kg DEX, but were not significantly reduced in Ad-injected mice pretreated with 0.1 mg/kg DEX. Finally, plasma levels of granulocyte colony–stimulating factor were only significantly reduced when Ad-injected mice were pr-treated with 10 mg/kg DEX (Figure 1). These results demonstrate that DEX pretreatment of animals can abrogate Ad induction of the “cytokine storm” noted after systemic delivery of Ad5-based vectors.21Appledorn DM McBride A Seregin S Scott JM Schuldt N Kiang A et al.Complex interactions with several arms of the complement system dictate innate and humoral immunity to adenoviral vectors.Gene Ther. 2008; 15: 1606-1617Crossref PubMed Scopus (62) Google Scholar Because pretreatment of mice with 10 mg/kg DEX maximally suppressed these responses, we evaluated the ability of this dose to further prevent the induction of other detrimental responses typically observed following systemic Ad vector administrations.DEX prevents Ad induction of thrombocytopenia in C57BL/6 miceNext, we determined whether DEX treatment could prevent the acute, consumptive thrombocytopenia typically observed within 24 hours after systemic Ad injection, an event that we have shown to be due to Ad activation of the alternative complement pathway.20Kiang A Hartman ZC Everett RS Serra D Jiang H Frank MM et al.Multiple innate inflammatory responses induced after systemic adenovirus vector delivery depend on a functional complement system.Mol Ther. 2006; 14: 588-598Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar,21Appledorn DM McBride A Seregin S Scott JM Schuldt N Kiang A et al.Complex interactions with several arms of the complement system dictate innate and humoral immunity to adenoviral vectors.Gene Ther. 2008; 15: 1606-1617Crossref PubMed Scopus (62) Google Scholar,22Wolins N Lozier J Eggerman TL Jones E Aguilar-Cordova E Vostal JG Intravenous administration of replication-incompetent adenovirus to rhesus monkeys induces thrombocytopenia by increasing in vivo platelet clearance.Br J Haematol. 2003; 123: 903-905Crossref PubMed Scopus (52) Google Scholar As expected, thrombocytopenia developed in WT mice treated with Ad5-LacZ (Figure 2). DEX pretreated mice did not develop thrombocytopenia after Ad injection, as their platelet levels were not different from mock-injected animals (Figure 2).Figure 2Dexamethasone (DEX) prevents Ad-mediated thrombocytopenia in C57BL/6 mice. C57BL/6 mice were intravenously injected with 0.75 × 1011 vp/mouse of Ad5-LacZ vector. DEX pretreatment and platelets enumerations were performed as described in Materials and Methods. Four groups of wild-type mice were analyzed: WT_Mock (N = 4), WT_DEX_Mock (N = 4), WT_Ad5-LacZ (N = 5), and WT_DEX_Ad5-LacZ (N = 5). The bars represent mean ± SD. Statistical analysis was completed using one-way analysis of variance with a Student–Newman–Keuls post hoc test; P < 0.05 was deemed a statistically significant difference. *,**Statistically different from those in WT_Mock–injected animals, P < 0.05 and P < 0.001, respectively. Note: Normal range levels were adapted from Jackson laboratories studies on C57BL/6 mice (http://phenome.jax.org/pub-cgi/phenome/mpdcgi?rtn=projects/details&sym=Peters3). WT, wild type.View Large Image Figure ViewerDownload Hi-res image Download (PPT)DEX minimizes Ad-dependent activation of endothelial cells in C57BL/6 miceEndothelial cell activation facilitates the infiltration of inflammatory cells, including macrophages, granulocytes and mast cells, into the parenchyma of inflamed tissues and organs. When endothelial cells become activated, they overexpress surface as well as soluble forms of adhesion molecules such as e-Selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1).23Li Y Muruve DA Collins RG Lee SS Kubes P The role of selectins and integrins in adenovirus vector-induced neutrophil recruitment to the liver.Eur J Immunol. 2002; 32: 3443-3452Crossref PubMed Scopus (33) Google Scholar,24Schiedner G Hertel S Kochanek S Efficient transformation of primary human amniocytes by E1 functions of Ad5: generation of new cell lines for adenoviral vector production.Hum Gene Ther. 2000; 11: 2105-2116Crossref PubMed Scopus (141) Google Scholar Intravenous injection of Ad vectors is known to induce endothelial cell activation, an event that is mediated by Ad interactions with Kupffer cells that can result in significant hypotension.25Schiedner G Bloch W Hertel S Johnston M Molojavyi A Dries V et al.A hemodynamic response to intravenous adenovirus vector particles is caused by systemic Kupffer cell-mediated activation of endothelial cells.Hum Gene Ther. 2003; 14: 1631-1641Crossref PubMed Scopus (91) Google Scholar We have measured plasma levels of soluble ICAM-1 and e-Selectin molecules in Ad-injected mice at 6 hpi. Ad-treated WT mice had at least threefold higher levels of soluble ICAM-1 and e-Selectin molecules than levels measured in mock-injected animals (Figure 3). DEX pretreatment completely blocked Ad-dependent activation of synthesis of these two molecules, indirectly demonstrating that DEX pretreatment can reduce the Ad-dependent activation of endothelial cells (Figure 3).Figure 3Dexamethasone (DEX) minimizes Ad-dependent activation of endothelial cells in C57BL/6 mice. DEX pretreated or nontreated C57BL/6 mice were intravenously injected with 0.75 × 1011 vp/mouse of Ad5-LacZ vector. Plasma samples, collected at 6 hpi (N = 6 for virus-treated groups, N = 4 for mock-injected groups) were analyzed using a multiplexed bead array–based quantitative system. The bars represent mean ± SD. Statistical analysis was completed using one-way analysis of variance with a Student–Newman–Keuls post hoc test. Fold difference over WT_Mock group is shown. *,**Statistically different from those in mock-injected animals of the same treatment, P < 0.05 and P < 0.001, respectively. #,##Statistically different values in any group compared to WT_Mock group, P < 0.05 and P < 0.001, respectively. ICAM-1, intercellular adhesion molecule 1; WT, wild type.View Large Image Figure ViewerDownload Hi-res image Download (PPT)DEX pretreatment minimizes the induction of proinflammatory genes in livers of Ad-treated C57BL/6 miceWe have previously and extensively characterized the cell or tissue-specific transcriptome changes rapidly induced after transduction by Ad vectors both in vitro and in vivo.20Kiang A Hartman ZC Everett RS Serra D Jiang H Frank MM et al.Multiple innate inflammatory responses induced after systemic adenovirus vector delivery depend on a functional complement system.Mol Ther. 2006; 14: 588-598Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar,26Hartman ZC Kiang A Everett RS Serra D Yang XY Clay TM et al.Adenovirus infection triggers a rapid, MyD88-regulated transcriptome response critical to acute-phase and adaptive immune responses in vivo.J Virol. 2007; 81: 1796-1812Crossref PubMed Scopus (126) Google Scholar,27Hartman ZC Black EP Amalfitano A Adenoviral infection induces a multi-faceted innate cellular immune response that is mediated by the toll-like receptor pathway in A549 cells.Virology. 2007; 358: 357-372Crossref PubMed Scopus (73) Google Scholar These studies revealed that Ads induce the expression of genes involved in innate immune responses, such as pattern recognition receptors (TLRs, nucleotide-binding oligomerization domains), TLR signaling pathways (myeloid differentiation factor-88, TIR-domain-containing adapter-inducing interferon-β, tumor necrosis factor receptor associated factor 6, tumor necrosis factor receptor associated factor 2bp, TANK-binding kinase 1), markers of endothelial cells activation (e-Selectin, ICAM-1, VCAM-1), interferon responsive genes (2′–5′ oligoadenylate synthetase, interferon regulatory factor 7, interferon regulatory factor 8), negative regulators of cytokine signaling (suppressor of cytokine signalling-1, suppressor of cytokine signalling-3), and dsRNA-editing enzymes (adenosine deaminase–RNA-specific).26Hartman ZC Kiang A Everett RS Serra D Yang XY Clay TM et al.Adenovirus infection triggers a rapid, MyD88-regulated transcriptome response critical to acute-phase and adaptive immune responses in vivo.J Virol. 2007; 81: 1796-1812Crossref PubMed Scopus (126) Google Scholar,27Hartman ZC Black EP Amalfitano A Adenoviral infection induces a multi-faceted innate cellular immune response that is mediated by the toll-like receptor pathway in A549 cells.Virology. 2007; 358: 357-372Crossref PubMed Scopus (73) Google Scholar We have also previously shown that in C57BL/6 mice, systemically administered Ads mediate induction of maximal liver transcription dysregulation at 6 hpi.26Hartman ZC Kiang A Everett RS Serra D Yang XY Clay TM et al.Adenovirus infection triggers a rapid, MyD88-regulated transcriptome response critical to acute-phase and adaptive immune responses in vivo.J Virol. 2007; 81: 1796-1812Crossref PubMed Scopus (126) Google Scholar Therefore, this time point was selected to determine whether pretreatment with DEX might block and/or minimize Ad vector induction of transcription of these proinflammatory genes (Table 1). Besides the genes mentioned above, we interrogated the expression of several additional genes: decay accelerating factor, potent membrane-bound complement inhibitor; NF-κB-RelA, subunit of transcription factor; Janus kinase 1 and Janus kinase 3, molecules involved in cytokine signaling in this assay. Thus, a total 23 genes were tested by quantitative reverse transcriptase (qRT)-PCR–based methods. Our results demonstrate that all of the genes tested (except interferon α) were significantly induced at 6 hpi in the livers of C57BL/6 mice systemically treated with Ad5-LacZ, as compared to mock-injected animals (P < 0.05), whereas only adenosine deaminase–RNA-specific and TLR3 were induced in DEX pretreated Ad5-LacZ–injected mice, as compared to mock-injected animals. Importantly, the level of transcription induction of all the genes except one was significantly reduced in virus-injected DEX pretreated mice, compared to the virus-treated group (P < 0.05, in vast majority of cases P < 0.001). Some of the genes in the DEX-treated, mock-infected groups of mice also had lower levels of transcription relative to mock-infected mice not treated with DEX, but in only five genes did this reach statistically significant levels: Janus kinase 1, Janus kinase 3, VCAM-1, nucleotide-binding oligomerization domain-1, and nucleotide-binding oligomerization domain-2, which indicates that several genes nonspecifically respond to DEX treatment. These data strongly indicate that despite the huge redundancy inherent to the Ad-induced host–transcriptome response mechanism, DEX can efficiently block all of these responses. Possibly, DEX can block transcription activation pathways and/or directly downregulate the transcription of proinflammatory genes typically responsive to glucocorticoid receptor (GR) activation, although post-transcriptional modifications altering RNA stability is a legitimate alternative explanation of DEX-mediated blockage of gene induction.28Huan" @default.
• W2086651005 created "2016-06-24" @default.
• W2086651005 creator A5003873927 @default.
• W2086651005 creator A5004667791 @default.
• W2086651005 creator A5008662619 @default.
• W2086651005 creator A5009576227 @default.
• W2086651005 creator A5016155646 @default.
• W2086651005 creator A5069284025 @default.
• W2086651005 creator A5070706150 @default.
• W2086651005 creator A5072833522 @default.
• W2086651005 creator A5074941403 @default.
• W2086651005 creator A5081577959 @default.
• W2086651005 creator A5083266436 @default.
• W2086651005 date "2009-04-01" @default.
• W2086651005 modified "2023-10-18" @default.
• W2086651005 title "Transient Pretreatment With Glucocorticoid Ablates Innate Toxicity of Systemically Delivered Adenoviral Vectors Without Reducing Efficacy" @default.
• W2086651005 cites W1519063308 @default.
• W2086651005 cites W1586130277 @default.
• W2086651005 cites W1963973005 @default.
• W2086651005 cites W1966694571 @default.
• W2086651005 cites W1970576711 @default.
• W2086651005 cites W1972301425 @default.
• W2086651005 cites W1982386968 @default.
• W2086651005 cites W1984592139 @default.
• W2086651005 cites W1995291792 @default.
• W2086651005 cites W1997110954 @default.
• W2086651005 cites W1998630678 @default.
• W2086651005 cites W2001489295 @default.
• W2086651005 cites W2006014143 @default.
• W2086651005 cites W2008260185 @default.
• W2086651005 cites W2012445117 @default.
• W2086651005 cites W2015930341 @default.
• W2086651005 cites W2022781751 @default.
• W2086651005 cites W2023985204 @default.
• W2086651005 cites W2029336962 @default.
• W2086651005 cites W2030899753 @default.
• W2086651005 cites W2031117040 @default.
• W2086651005 cites W2032870583 @default.
• W2086651005 cites W2034106065 @default.
• W2086651005 cites W2041247227 @default.
• W2086651005 cites W2044338251 @default.
• W2086651005 cites W2046822617 @default.
• W2086651005 cites W2056810047 @default.
• W2086651005 cites W2058830142 @default.
• W2086651005 cites W2070280791 @default.
• W2086651005 cites W2072160274 @default.
• W2086651005 cites W2075338937 @default.
• W2086651005 cites W2078519091 @default.
• W2086651005 cites W2079861804 @default.
• W2086651005 cites W2091376729 @default.
• W2086651005 cites W2092960442 @default.
• W2086651005 cites W2094593077 @default.
• W2086651005 cites W2097831531 @default.
• W2086651005 cites W2106008384 @default.
• W2086651005 cites W2112383089 @default.
• W2086651005 cites W2119822849 @default.
• W2086651005 cites W2122033091 @default.
• W2086651005 cites W2140282212 @default.
• W2086651005 cites W2140631766 @default.
• W2086651005 cites W2146611590 @default.
• W2086651005 cites W2147451793 @default.
• W2086651005 cites W2160517494 @default.
• W2086651005 cites W2163192616 @default.
• W2086651005 cites W2163995770 @default.
• W2086651005 cites W2167125445 @default.
• W2086651005 doi "https://doi.org/10.1038/mt.2008.297" @default.
• W2086651005 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2835110" @default.
• W2086651005 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/19174760" @default.
• W2086651005 hasPublicationYear "2009" @default.
• W2086651005 type Work @default.
• W2086651005 sameAs 2086651005 @default.
• W2086651005 citedByCount "90" @default.
• W2086651005 countsByYear W20866510052012 @default.
• W2086651005 countsByYear W20866510052013 @default.
• W2086651005 countsByYear W20866510052014 @default.
• W2086651005 countsByYear W20866510052015 @default.
• W2086651005 countsByYear W20866510052016 @default.
• W2086651005 countsByYear W20866510052017 @default.
• W2086651005 countsByYear W20866510052018 @default.
• W2086651005 countsByYear W20866510052019 @default.
• W2086651005 countsByYear W20866510052020 @default.
• W2086651005 countsByYear W20866510052021 @default.
• W2086651005 countsByYear W20866510052022 @default.
• W2086651005 countsByYear W20866510052023 @default.
• W2086651005 crossrefType "journal-article" @default.
• W2086651005 hasAuthorship W2086651005A5003873927 @default.
• W2086651005 hasAuthorship W2086651005A5004667791 @default.
• W2086651005 hasAuthorship W2086651005A5008662619 @default.
• W2086651005 hasAuthorship W2086651005A5009576227 @default.
• W2086651005 hasAuthorship W2086651005A5016155646 @default.
• W2086651005 hasAuthorship W2086651005A5069284025 @default.
• W2086651005 hasAuthorship W2086651005A5070706150 @default.
• W2086651005 hasAuthorship W2086651005A5072833522 @default.
• W2086651005 hasAuthorship W2086651005A5074941403 @default.
• W2086651005 hasAuthorship W2086651005A5081577959 @default.
• W2086651005 hasAuthorship W2086651005A5083266436 @default.
• W2086651005 hasBestOaLocation W20866510051 @default.
• W2086651005 hasConcept C111919701 @default.

• next