Hepatic DR5 Induces Apoptosis and Limits Adenovirus Gene Therapy Product Expression in the Liver

Zhang, Huang‐Ge; Xie, Jinfu; Xu, Liang; Yang, PingAr; Xu, Xin; Sun, Sheher; Wang, Yongming; Curiel, David T.; Hsu, Hui‐Chen; Mountz, John D.

doi:10.1128/jvi.76.11.5692-5700.2002

Cited by 34 publications

(28 citation statements)

References 54 publications

(56 reference statements)

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“…This has been reported for adenoviral gene transfer of the lacZ gene to the liver, [12][13][14] and seemed a logical hypothesis for the sec-R-directed gene transfer, because many of the cells to which the foreign gene is delivered are macrophages, which are known antigen-presenting cells. The time course of gene expression from sec-R-directed gene transfer is also consistent with this hypothesis, for cytotoxic lymphocytes arise about 2-4 weeks after challenge.…”

Section: Discussionmentioning

confidence: 82%

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Defining strategies to extend duration of gene expression from targeted compacted DNA vectors

et al. 2004

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Gene transfer complexes containing poly-L-lysine (poly-K) and DNA with ligands directed at the serpin enzyme complex receptor (sec-R) deliver reporter genes to receptor-bearing cells in vivo. Expression lasts for about 30 days, when complexes containing long-chain poly-K are used. Extending the duration of expression would be desirable if correction of genetic defects is the goal. To test whether the mechanism by which expression is extinguished was due to an immune response to the transgene, or the loss of the transgene, we conducted two experiments. In the first, we injected sec-Rtargeted lacZ complexes intravenously (i.v.) into mice genetically engineered to express this gene briefly during development. These mice, who should recognize the protein as 'self', also extinguished lacZ expression after 30 days. In a second experiment, we injected immunodeficient animals with sec-R-targeted human factor IX complexes. A similar temporal pattern of expression was observed in Rag-1 À/À mice, in whom expression also extinguished by 40 days. Moreover, factor IX plasmid DNA was detected in the lung and spleen 50 days after injection of complexes, suggesting that not all cells which had taken up the transgene had been destroyed. Thus, the host's immune response to the transgene may not account for the loss of reporter gene expression from these molecular conjugates. We further tested whether repeat administration of sec-R-targeted complexes will be limited by host immune responses. Mice were pre-dosed twice with sec-R-targeted complexes containing lacZ over a 40-day period. We then injected the animals i.v. with sec-R-targeted human factor IX complexes and measured gene expression and antibody production. Although 14 of 36 animals displayed low-titer antibodies to the ligand in targeted complex, expression levels were unaffected compared with virgin dosing. When the complexes were administered three times intranasally (n ¼ 10), no antibodies against the complex were detected in blood. Plasma from mice dosed with saline, nontargeted complex or naked DNA did not react with the ligand, ligand-poly K conjugate or targeted complex. All animals exhibiting human factor IX expression developed antibodies to that transgene by 21 days. Thus, at least three repeat administrations of sec-R-directed molecular conjugates are possible, provided that immune responses to the transgene itself are not limiting.

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Section: Discussionmentioning

confidence: 82%

“…This contrasts with reports of adenoviral gene transfer in which cellular infiltrates about transfected cells are regularly observed. [12][13]22 The failure of the complex to induce a 'danger' signal in the vicinity of the transfected cells may reduce the host's immune response to the transgene.…”

Section: Discussionmentioning

confidence: 99%

Defining strategies to extend duration of gene expression from targeted compacted DNA vectors

et al. 2004

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“…13 Briefly, spleens and lungs were disrupted using wire mesh screens, and erythrocytes were lysed by treatment with buffered-NH 4 Cl (8.29 g of NH 4 Cl, 1.0 g of KHCO 3 , and 0.037 g of EDTA/l). The livers were strained through a 70 mm nylon cell screen (BD Falcon, Bedford, MA, USA).…”

Section: Cell Preparationmentioning

confidence: 99%

“…13 Infected cells were harvested and lysed by three freeze-thaw cycles to release the virus, which was then purified through two cesium chloride gradients. The purified wild-type Ad5 was then titrated by the plaque assay, 45 aliquoted, and stored at À801C until used.…”

Section: Ad and Infectionmentioning

confidence: 99%

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Primary adenovirus-specific cytotoxic T lymphocyte response occurs after viral clearance and liver enzyme elevation

Chen

et al. 2005

Gene Ther

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The virus-specific cytotoxic T lymphocyte (CTL) response is a major obstacle to effective delivery of adenovirus gene therapy. However, its relative role in viral clearance, transgene elimination and hepatotoxicity remains unclear. In this paper, we present an analysis of viral clearance and liver toxicity in relation to the induction of the virus-specific CD8 T-cell response revealed by an MHC class I tetramer. A surprisingly high number of tetramer + CD8 T cells were found in the liver and lung and reached peak values at days 8 and 10, respectively, post-infection. Nearly 100% of these tetramer + CD8 T cells expressed high levels of granzyme B and IFNg. Remarkably, liver viral load and liver enzyme elevation peaked early, at days 2 and 4, respectively, postinfection, before the specific CTL response was detectable. After generation of CTLs, there was only minimal liver damage or further decrease in virus titer. These results indicated that the primary peak response of tetramer + CTLs does not correlate with the elimination of adenovirus or liver cytotoxic response.

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Immunological Features of AECHB

Lei

Shen

Wang

et al. 2019

Acute Exacerbation of Chronic Hepatitis B

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Hepatic DR5 Induces Apoptosis and Limits Adenovirus Gene Therapy Product Expression in the Liver

Cited by 34 publications

References 54 publications

Defining strategies to extend duration of gene expression from targeted compacted DNA vectors

Defining strategies to extend duration of gene expression from targeted compacted DNA vectors

Primary adenovirus-specific cytotoxic T lymphocyte response occurs after viral clearance and liver enzyme elevation

Immunological Features of AECHB

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