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The role of capsid-endothelial interactions in the innate immune response to adenovirus vectors.
Hum Gene Ther. 2003 May 01; 14(7):627-43.HG

Abstract

Adenovirus (Ad) vectors can produce inflammatory responses at high doses. Intravenous administration of an Ad vector expressing green fluorescent protein (AdGFP) to naive mice induced a biphasic pattern of liver cytokine/chemokine gene expression over 7 days. Tumor necrosis factor alpha (TNF-alpha), macrophage inflammatory protein 2 (MIP-2), and interferon gamma-inducible protein 10 (IP-10) genes were upregulated, with two distinct peaks of mRNA expression occurring at 6 hr and 5 days. The administration of transcription-defective AdGFP particles induced the early but not the late peak of chemokine/cytokine gene expression, confirming that Ad vector-induced inflammation is capsid dependent in the early phase and transcription dependent in the late phase. To determine the role of adenoviral capsid motifs in the early phase, capsid-modified Ad vectors were employed. The intravenous administration of the RGD-deleted Ad vector AdL.PB*, the fiber mutant AdL.F*, or the double mutant AdL.F*PB* induced similar levels of cytokine/chemokine expression compared with the wild-type vector AdLuc. Kupffer cell blockade significantly reduced liver TNF-alpha, MIP-2, and IP-10 gene expression and liver inflammation after the administration of AdL.PB* or AdL.F*PB*. Fluorescence microscopy of AdLuc- and AdL.PB*-transduced liver at 1 hr revealed localization of Ad vectors to liver sinusoids in Kupffer cell-depleted mice. AdL.PB* induced less E-selectin and VCAM-1 gene expression in liver, confirming reduced endothelial activation in mice receiving RGD-deleted Ad vectors. In vitro studies of endothelial cells demonstrated reduced transduction and endothelial activation by AdL.PB* compared with AdLuc. These results demonstrate that adenovirus capsid RGD motifs are required for efficient transduction and endothelial cell activation. Altering vector tropism represents a feasible strategy to modulate the innate response to Ad vectors in nontargeted tissues.

Authors+Show Affiliations

Department of Medicine, University of Calgary, Calgary, Alberta, T2N 4N1 Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12804145

Citation

Liu, Qiang, et al. "The Role of Capsid-endothelial Interactions in the Innate Immune Response to Adenovirus Vectors." Human Gene Therapy, vol. 14, no. 7, 2003, pp. 627-43.
Liu Q, Zaiss AK, Colarusso P, et al. The role of capsid-endothelial interactions in the innate immune response to adenovirus vectors. Hum Gene Ther. 2003;14(7):627-43.
Liu, Q., Zaiss, A. K., Colarusso, P., Patel, K., Haljan, G., Wickham, T. J., & Muruve, D. A. (2003). The role of capsid-endothelial interactions in the innate immune response to adenovirus vectors. Human Gene Therapy, 14(7), 627-43.
Liu Q, et al. The Role of Capsid-endothelial Interactions in the Innate Immune Response to Adenovirus Vectors. Hum Gene Ther. 2003 May 1;14(7):627-43. PubMed PMID: 12804145.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The role of capsid-endothelial interactions in the innate immune response to adenovirus vectors. AU - Liu,Qiang, AU - Zaiss,Anne K, AU - Colarusso,Pina, AU - Patel,Kamala, AU - Haljan,Gregory, AU - Wickham,Thomas J, AU - Muruve,Daniel A, PY - 2003/6/14/pubmed PY - 2003/10/3/medline PY - 2003/6/14/entrez SP - 627 EP - 43 JF - Human gene therapy JO - Hum Gene Ther VL - 14 IS - 7 N2 - Adenovirus (Ad) vectors can produce inflammatory responses at high doses. Intravenous administration of an Ad vector expressing green fluorescent protein (AdGFP) to naive mice induced a biphasic pattern of liver cytokine/chemokine gene expression over 7 days. Tumor necrosis factor alpha (TNF-alpha), macrophage inflammatory protein 2 (MIP-2), and interferon gamma-inducible protein 10 (IP-10) genes were upregulated, with two distinct peaks of mRNA expression occurring at 6 hr and 5 days. The administration of transcription-defective AdGFP particles induced the early but not the late peak of chemokine/cytokine gene expression, confirming that Ad vector-induced inflammation is capsid dependent in the early phase and transcription dependent in the late phase. To determine the role of adenoviral capsid motifs in the early phase, capsid-modified Ad vectors were employed. The intravenous administration of the RGD-deleted Ad vector AdL.PB*, the fiber mutant AdL.F*, or the double mutant AdL.F*PB* induced similar levels of cytokine/chemokine expression compared with the wild-type vector AdLuc. Kupffer cell blockade significantly reduced liver TNF-alpha, MIP-2, and IP-10 gene expression and liver inflammation after the administration of AdL.PB* or AdL.F*PB*. Fluorescence microscopy of AdLuc- and AdL.PB*-transduced liver at 1 hr revealed localization of Ad vectors to liver sinusoids in Kupffer cell-depleted mice. AdL.PB* induced less E-selectin and VCAM-1 gene expression in liver, confirming reduced endothelial activation in mice receiving RGD-deleted Ad vectors. In vitro studies of endothelial cells demonstrated reduced transduction and endothelial activation by AdL.PB* compared with AdLuc. These results demonstrate that adenovirus capsid RGD motifs are required for efficient transduction and endothelial cell activation. Altering vector tropism represents a feasible strategy to modulate the innate response to Ad vectors in nontargeted tissues. SN - 1043-0342 UR - https://www.unboundmedicine.com/medline/citation/12804145/The_role_of_capsid_endothelial_interactions_in_the_innate_immune_response_to_adenovirus_vectors_ L2 - https://www.liebertpub.com/doi/10.1089/104303403321618146?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -