Tumor necrosis factor α plays a central role in immune-mediated clearance of adenoviral vectors

Keith B. Elkon, Chau Ching Liu, Jason G. Gall, Jose Trevejo, Michael W. Marino, Karil A. Abrahamsen, Xin Song, Jun Liang Zhou, Lloyd J. Old, Ronald Crystal, Erik Falck-Pedersen

Research output: Contribution to journalArticle

124 Citations (Scopus)

Abstract

Adenovirus (Ad) gene transfer vectors are rapidly cleared from infected hepatocytes in mice. To determine which effector mechanisms are responsible for elimination of the Ad vectors, we infected mice that were genetically compromised in immune effector pathways [perforin, Fas, or tumor necrosis factor α (TNF-α)] with the Ad vector, Ad5-chloramphenicol acetyl transferase (CAT). Mice were sacrificed at 7-60 days postinfection, and the levels of CAT expression in the liver determined by a quantitative enzymatic assay. When the livers of infected mice were harvested 28 days postinfection, the levels of CAT expression revealed that the effectors most important for the elimination of the Ad vector were TNF-α > Fas > perforin. TNF-α did not have a curative effect on infected hepatocytes, as the administration of TNF- α to infected severe combined immunodeficient mice or to infected cultures in vitro had no specific effect on virus persistence. However, TNF-α- deficient mice demonstrated a striking reduction in the leukocytic infiltration early on in the infection, suggesting that TNF-α deficiency resulted in impaired recruitment of inflammatory cells to the site of inflammation. In addition, the TNF-deficient mice had a significantly reduced humoral immune response to virus infection. These results demonstrate a dominant role of TNF-α in elimination of Ad gene transfer vectors. This result is particularly important because viral proteins that disable TNF-α function have been removed from most Ad vectors, rendering them highly susceptible to TNF-α-mediated elimination.

Original languageEnglish
Pages (from-to)9814-9819
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number18
DOIs
Publication statusPublished - 2 Sep 1997
Externally publishedYes

Fingerprint

Tumor Necrosis Factor-alpha
Adenoviridae
Chloramphenicol
Transferases
Perforin
Hepatocytes
SCID Mice
Liver
Enzyme Assays
Viral Proteins
Virus Diseases
Humoral Immunity
Genes
Viruses
Inflammation
Infection

ASJC Scopus subject areas

  • General

Cite this

Tumor necrosis factor α plays a central role in immune-mediated clearance of adenoviral vectors. / Elkon, Keith B.; Liu, Chau Ching; Gall, Jason G.; Trevejo, Jose; Marino, Michael W.; Abrahamsen, Karil A.; Song, Xin; Zhou, Jun Liang; Old, Lloyd J.; Crystal, Ronald; Falck-Pedersen, Erik.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 94, No. 18, 02.09.1997, p. 9814-9819.

Research output: Contribution to journalArticle

Elkon, KB, Liu, CC, Gall, JG, Trevejo, J, Marino, MW, Abrahamsen, KA, Song, X, Zhou, JL, Old, LJ, Crystal, R & Falck-Pedersen, E 1997, 'Tumor necrosis factor α plays a central role in immune-mediated clearance of adenoviral vectors', Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 18, pp. 9814-9819. https://doi.org/10.1073/pnas.94.18.9814
Elkon, Keith B. ; Liu, Chau Ching ; Gall, Jason G. ; Trevejo, Jose ; Marino, Michael W. ; Abrahamsen, Karil A. ; Song, Xin ; Zhou, Jun Liang ; Old, Lloyd J. ; Crystal, Ronald ; Falck-Pedersen, Erik. / Tumor necrosis factor α plays a central role in immune-mediated clearance of adenoviral vectors. In: Proceedings of the National Academy of Sciences of the United States of America. 1997 ; Vol. 94, No. 18. pp. 9814-9819.
@article{60287abad59a439a88c6ad779cba6caf,
title = "Tumor necrosis factor α plays a central role in immune-mediated clearance of adenoviral vectors",
abstract = "Adenovirus (Ad) gene transfer vectors are rapidly cleared from infected hepatocytes in mice. To determine which effector mechanisms are responsible for elimination of the Ad vectors, we infected mice that were genetically compromised in immune effector pathways [perforin, Fas, or tumor necrosis factor α (TNF-α)] with the Ad vector, Ad5-chloramphenicol acetyl transferase (CAT). Mice were sacrificed at 7-60 days postinfection, and the levels of CAT expression in the liver determined by a quantitative enzymatic assay. When the livers of infected mice were harvested 28 days postinfection, the levels of CAT expression revealed that the effectors most important for the elimination of the Ad vector were TNF-α > Fas > perforin. TNF-α did not have a curative effect on infected hepatocytes, as the administration of TNF- α to infected severe combined immunodeficient mice or to infected cultures in vitro had no specific effect on virus persistence. However, TNF-α- deficient mice demonstrated a striking reduction in the leukocytic infiltration early on in the infection, suggesting that TNF-α deficiency resulted in impaired recruitment of inflammatory cells to the site of inflammation. In addition, the TNF-deficient mice had a significantly reduced humoral immune response to virus infection. These results demonstrate a dominant role of TNF-α in elimination of Ad gene transfer vectors. This result is particularly important because viral proteins that disable TNF-α function have been removed from most Ad vectors, rendering them highly susceptible to TNF-α-mediated elimination.",
author = "Elkon, {Keith B.} and Liu, {Chau Ching} and Gall, {Jason G.} and Jose Trevejo and Marino, {Michael W.} and Abrahamsen, {Karil A.} and Xin Song and Zhou, {Jun Liang} and Old, {Lloyd J.} and Ronald Crystal and Erik Falck-Pedersen",
year = "1997",
month = "9",
day = "2",
doi = "10.1073/pnas.94.18.9814",
language = "English",
volume = "94",
pages = "9814--9819",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "18",

}

TY - JOUR

T1 - Tumor necrosis factor α plays a central role in immune-mediated clearance of adenoviral vectors

AU - Elkon, Keith B.

AU - Liu, Chau Ching

AU - Gall, Jason G.

AU - Trevejo, Jose

AU - Marino, Michael W.

AU - Abrahamsen, Karil A.

AU - Song, Xin

AU - Zhou, Jun Liang

AU - Old, Lloyd J.

AU - Crystal, Ronald

AU - Falck-Pedersen, Erik

PY - 1997/9/2

Y1 - 1997/9/2

N2 - Adenovirus (Ad) gene transfer vectors are rapidly cleared from infected hepatocytes in mice. To determine which effector mechanisms are responsible for elimination of the Ad vectors, we infected mice that were genetically compromised in immune effector pathways [perforin, Fas, or tumor necrosis factor α (TNF-α)] with the Ad vector, Ad5-chloramphenicol acetyl transferase (CAT). Mice were sacrificed at 7-60 days postinfection, and the levels of CAT expression in the liver determined by a quantitative enzymatic assay. When the livers of infected mice were harvested 28 days postinfection, the levels of CAT expression revealed that the effectors most important for the elimination of the Ad vector were TNF-α > Fas > perforin. TNF-α did not have a curative effect on infected hepatocytes, as the administration of TNF- α to infected severe combined immunodeficient mice or to infected cultures in vitro had no specific effect on virus persistence. However, TNF-α- deficient mice demonstrated a striking reduction in the leukocytic infiltration early on in the infection, suggesting that TNF-α deficiency resulted in impaired recruitment of inflammatory cells to the site of inflammation. In addition, the TNF-deficient mice had a significantly reduced humoral immune response to virus infection. These results demonstrate a dominant role of TNF-α in elimination of Ad gene transfer vectors. This result is particularly important because viral proteins that disable TNF-α function have been removed from most Ad vectors, rendering them highly susceptible to TNF-α-mediated elimination.

AB - Adenovirus (Ad) gene transfer vectors are rapidly cleared from infected hepatocytes in mice. To determine which effector mechanisms are responsible for elimination of the Ad vectors, we infected mice that were genetically compromised in immune effector pathways [perforin, Fas, or tumor necrosis factor α (TNF-α)] with the Ad vector, Ad5-chloramphenicol acetyl transferase (CAT). Mice were sacrificed at 7-60 days postinfection, and the levels of CAT expression in the liver determined by a quantitative enzymatic assay. When the livers of infected mice were harvested 28 days postinfection, the levels of CAT expression revealed that the effectors most important for the elimination of the Ad vector were TNF-α > Fas > perforin. TNF-α did not have a curative effect on infected hepatocytes, as the administration of TNF- α to infected severe combined immunodeficient mice or to infected cultures in vitro had no specific effect on virus persistence. However, TNF-α- deficient mice demonstrated a striking reduction in the leukocytic infiltration early on in the infection, suggesting that TNF-α deficiency resulted in impaired recruitment of inflammatory cells to the site of inflammation. In addition, the TNF-deficient mice had a significantly reduced humoral immune response to virus infection. These results demonstrate a dominant role of TNF-α in elimination of Ad gene transfer vectors. This result is particularly important because viral proteins that disable TNF-α function have been removed from most Ad vectors, rendering them highly susceptible to TNF-α-mediated elimination.

UR - http://www.scopus.com/inward/record.url?scp=12644314130&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=12644314130&partnerID=8YFLogxK

U2 - 10.1073/pnas.94.18.9814

DO - 10.1073/pnas.94.18.9814

M3 - Article

C2 - 9275208

AN - SCOPUS:12644314130

VL - 94

SP - 9814

EP - 9819

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 18

ER -