Innate Immune Response to Adenovirus

Nazir, Shoab A.; Metcalf, Jordan P.

doi:10.2310/6650.2005.53605

Cited by 43 publications

(29 citation statements)

References 166 publications

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“…In the present study, although AdK7-L2 mediated higher luciferase expression and a higher accumulation of viral DNA in the liver than Ad-L2, it remains unclear why AdK7-L2 showed almost background levels of liver toxicity while Ad-L2 showed high toxicity. As reported previously, inflammatory cytokines, chemokines, and IFNs could be the mediators responsible for liver toxicity (2). IL-6 levels in the serum were the most strikingly different between AdK7-L2 and Ad-L2.…”

Section: Elimination Of Il-6 Signaling Reduces Liver Toxicitysupporting

confidence: 71%

“…1), the transduction and distribution of the vector into the liver did not participate in liver toxicity. The cytokines/chemokines play a major causative role in liver damage associated with systemic Ad infusion as well as in the induction of an antiviral immune response (2). Ad-induced cytokines/chemokines recruit immune effector cells (neutrophils, monocyte/macrophages, and NK cells) to Ad-transduced cells (mainly liver), resulting in acute hepatic toxicity.…”

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: Elimination Of Il-6 Signaling Reduces Liver Toxicitysupporting

confidence: 71%

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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“…First, the immune response elicited from the vector limits transgene expression [17,18], yet the local inflammatory response can potentially influence regeneration [19][20][21][22]. The extent of the immune response can determine whether the vector could be delivered more than once.…”

Section: Vector Designmentioning

confidence: 99%

Matrices and scaffolds for DNA delivery in tissue engineering

Laporte¹,

Shea²

2007

Advanced Drug Delivery Reviews

240

208

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Regenerative medicine aims to create functional tissue replacements, typically through creating a controlled environment that promotes and directs the differentiation of stem or progenitor cells, either endogenous or transplanted. Scaffolds serve a central role in many strategies by providing the means to control the local environment. Gene delivery from the scaffold represents a versatile approach to manipulating the local environment for directing cell function. Research at the interface of biomaterials, gene therapy, and drug delivery has identified several design parameters for the vector and the biomaterial scaffold that must be satisfied. Progress has been made towards achieving gene delivery within a tissue engineering scaffold, though the design principles for the materials and vectors that produce efficient delivery require further development. Nevertheless, these advances in obtaining transgene expression with the scaffold have created opportunities to develop greater control of either delivery or expression and to identify the best practices for promoting tissue formation. Strategies to achieve controlled localized expression within the tissue engineering scaffold will have broad application to the regeneration of many tissues, with great promise for clinical therapies.

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“…175 Ad-based vaccines have been shown to produce strong T-and B-cell responses to the transgene, and therefore already contain a powerful adjuvant within the vaccine vector. 121 Currently, the immunological correlates of protection necessary for survival upon filovirus infection may need to be better understood before selecting an adjuvant for the vaccine candidates.…”

Section: Routes Of Vaccination and Ease Of Administrationmentioning

confidence: 99%

“…Recombinant AdHu5 vectors are characterized by the ability of the virus to elicit a strong immune response, making adenovirus-based vectors attractive vaccine carriers. 121 The initial success generated from boosting a DNA vaccine combining ZEBOV GP + ZEBOV NP + SEBOV GP + ICEBOV GP with an additional booster injection of recombinant adenovirus expressing ZEBOV GP (AdHu5-ZGP) has encouraged the development of more replication-deficient adenovirus-based strategies. 102 It should be noted that subsequent studies suggest that the DNA portion of this prime-boost approach is not necessary to provide protection and, indeed, is not protective when given singly.…”

mentioning

confidence: 99%