TNF-α receptor signaling and IL-10 gene therapy regulate the innate and humoral immune responses to recombinant adenovirus in the lung

Rebecca M. Minter, John E. Rectenwald, Kunitaro Fukuzuka, Cynthia L. Tannahill, Drake La Face, Van Tsai, Iqbal Ahmed, Elizabeth Hutchins, Richard Moyer, Edward M. Copeland, Lyle L. Moldawer

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Recombinant adenovirus-mediated gene therapy has demonstrated great promise for the delivery of genes to the pulmonary epithelium. However, dose- dependent inflammation and local immune responses abbreviate transgene expression. The purpose of these studies was to determine the role of TNF-α and individual TNF receptor signaling to adenovirus clearance and immune responses, and whether coexpression of human IL-10 could reduce inflammation and extend the duration of transgene expression in the lung. β-Galactosidase expression in mice receiving intratracheal instillation of Adv/β-gal (adenovirus construct expressing β-galactosidase) was transient (less than 14 days), but a significant early increase of β-galactosidase expression was seen in mice lacking either or both TNF-α receptors. Absence of TNF-α or the p55 receptor significantly attenuated the Ab response to both adenovirus and β-galactosidase. Human IL-10 expression in the lung suppressed local TNF-α production following AdV/hIL-10 (adenovirus construct expressing human IL-10) delivery, but did not lead to increased or prolonged transgene expression when coexpressed with β-galactosidase. Expression of human IL-10 following AdV/hIL-10 instillation extended at least 14 days, was nonimmunogenic, and suppressed the development of neutralizing Abs against adenoviral proteins as well as against human IL-10. We conclude that TNF-α signaling through both the p55 and p75 receptor plays important roles in the clearance of adenoviral vectors and the magnitude of the humoral immune response. Additionally, although coexpression of human IL-10 with β- galactosidase had only modest effects on transgene expression, we demonstrate that AdV/hIL-10 is well tolerated, has extended expression compared with β- galactosidase, and is nonimmunogenic in the lung.

Original languageEnglish (US)
Pages (from-to)443-451
Number of pages9
JournalJournal of Immunology
Volume164
Issue number1
StatePublished - Jan 1 2000

Fingerprint

Galactosidases
Tumor Necrosis Factor Receptors
Humoral Immunity
Innate Immunity
Adenoviridae
Genetic Therapy
Interleukin-10
Lung
Transgenes
Inflammation
Epithelium

ASJC Scopus subject areas

  • Immunology

Cite this

TNF-α receptor signaling and IL-10 gene therapy regulate the innate and humoral immune responses to recombinant adenovirus in the lung. / Minter, Rebecca M.; Rectenwald, John E.; Fukuzuka, Kunitaro; Tannahill, Cynthia L.; La Face, Drake; Tsai, Van; Ahmed, Iqbal; Hutchins, Elizabeth; Moyer, Richard; Copeland, Edward M.; Moldawer, Lyle L.

In: Journal of Immunology, Vol. 164, No. 1, 01.01.2000, p. 443-451.

Research output: Contribution to journalArticle

Minter, RM, Rectenwald, JE, Fukuzuka, K, Tannahill, CL, La Face, D, Tsai, V, Ahmed, I, Hutchins, E, Moyer, R, Copeland, EM & Moldawer, LL 2000, 'TNF-α receptor signaling and IL-10 gene therapy regulate the innate and humoral immune responses to recombinant adenovirus in the lung', Journal of Immunology, vol. 164, no. 1, pp. 443-451.
Minter, Rebecca M. ; Rectenwald, John E. ; Fukuzuka, Kunitaro ; Tannahill, Cynthia L. ; La Face, Drake ; Tsai, Van ; Ahmed, Iqbal ; Hutchins, Elizabeth ; Moyer, Richard ; Copeland, Edward M. ; Moldawer, Lyle L. / TNF-α receptor signaling and IL-10 gene therapy regulate the innate and humoral immune responses to recombinant adenovirus in the lung. In: Journal of Immunology. 2000 ; Vol. 164, No. 1. pp. 443-451.
@article{05c289ad08e3426ca89ef04928b589b3,
title = "TNF-α receptor signaling and IL-10 gene therapy regulate the innate and humoral immune responses to recombinant adenovirus in the lung",
abstract = "Recombinant adenovirus-mediated gene therapy has demonstrated great promise for the delivery of genes to the pulmonary epithelium. However, dose- dependent inflammation and local immune responses abbreviate transgene expression. The purpose of these studies was to determine the role of TNF-α and individual TNF receptor signaling to adenovirus clearance and immune responses, and whether coexpression of human IL-10 could reduce inflammation and extend the duration of transgene expression in the lung. β-Galactosidase expression in mice receiving intratracheal instillation of Adv/β-gal (adenovirus construct expressing β-galactosidase) was transient (less than 14 days), but a significant early increase of β-galactosidase expression was seen in mice lacking either or both TNF-α receptors. Absence of TNF-α or the p55 receptor significantly attenuated the Ab response to both adenovirus and β-galactosidase. Human IL-10 expression in the lung suppressed local TNF-α production following AdV/hIL-10 (adenovirus construct expressing human IL-10) delivery, but did not lead to increased or prolonged transgene expression when coexpressed with β-galactosidase. Expression of human IL-10 following AdV/hIL-10 instillation extended at least 14 days, was nonimmunogenic, and suppressed the development of neutralizing Abs against adenoviral proteins as well as against human IL-10. We conclude that TNF-α signaling through both the p55 and p75 receptor plays important roles in the clearance of adenoviral vectors and the magnitude of the humoral immune response. Additionally, although coexpression of human IL-10 with β- galactosidase had only modest effects on transgene expression, we demonstrate that AdV/hIL-10 is well tolerated, has extended expression compared with β- galactosidase, and is nonimmunogenic in the lung.",
author = "Minter, {Rebecca M.} and Rectenwald, {John E.} and Kunitaro Fukuzuka and Tannahill, {Cynthia L.} and {La Face}, Drake and Van Tsai and Iqbal Ahmed and Elizabeth Hutchins and Richard Moyer and Copeland, {Edward M.} and Moldawer, {Lyle L.}",
year = "2000",
month = "1",
day = "1",
language = "English (US)",
volume = "164",
pages = "443--451",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "1",

}

TY - JOUR

T1 - TNF-α receptor signaling and IL-10 gene therapy regulate the innate and humoral immune responses to recombinant adenovirus in the lung

AU - Minter, Rebecca M.

AU - Rectenwald, John E.

AU - Fukuzuka, Kunitaro

AU - Tannahill, Cynthia L.

AU - La Face, Drake

AU - Tsai, Van

AU - Ahmed, Iqbal

AU - Hutchins, Elizabeth

AU - Moyer, Richard

AU - Copeland, Edward M.

AU - Moldawer, Lyle L.

PY - 2000/1/1

Y1 - 2000/1/1

N2 - Recombinant adenovirus-mediated gene therapy has demonstrated great promise for the delivery of genes to the pulmonary epithelium. However, dose- dependent inflammation and local immune responses abbreviate transgene expression. The purpose of these studies was to determine the role of TNF-α and individual TNF receptor signaling to adenovirus clearance and immune responses, and whether coexpression of human IL-10 could reduce inflammation and extend the duration of transgene expression in the lung. β-Galactosidase expression in mice receiving intratracheal instillation of Adv/β-gal (adenovirus construct expressing β-galactosidase) was transient (less than 14 days), but a significant early increase of β-galactosidase expression was seen in mice lacking either or both TNF-α receptors. Absence of TNF-α or the p55 receptor significantly attenuated the Ab response to both adenovirus and β-galactosidase. Human IL-10 expression in the lung suppressed local TNF-α production following AdV/hIL-10 (adenovirus construct expressing human IL-10) delivery, but did not lead to increased or prolonged transgene expression when coexpressed with β-galactosidase. Expression of human IL-10 following AdV/hIL-10 instillation extended at least 14 days, was nonimmunogenic, and suppressed the development of neutralizing Abs against adenoviral proteins as well as against human IL-10. We conclude that TNF-α signaling through both the p55 and p75 receptor plays important roles in the clearance of adenoviral vectors and the magnitude of the humoral immune response. Additionally, although coexpression of human IL-10 with β- galactosidase had only modest effects on transgene expression, we demonstrate that AdV/hIL-10 is well tolerated, has extended expression compared with β- galactosidase, and is nonimmunogenic in the lung.

AB - Recombinant adenovirus-mediated gene therapy has demonstrated great promise for the delivery of genes to the pulmonary epithelium. However, dose- dependent inflammation and local immune responses abbreviate transgene expression. The purpose of these studies was to determine the role of TNF-α and individual TNF receptor signaling to adenovirus clearance and immune responses, and whether coexpression of human IL-10 could reduce inflammation and extend the duration of transgene expression in the lung. β-Galactosidase expression in mice receiving intratracheal instillation of Adv/β-gal (adenovirus construct expressing β-galactosidase) was transient (less than 14 days), but a significant early increase of β-galactosidase expression was seen in mice lacking either or both TNF-α receptors. Absence of TNF-α or the p55 receptor significantly attenuated the Ab response to both adenovirus and β-galactosidase. Human IL-10 expression in the lung suppressed local TNF-α production following AdV/hIL-10 (adenovirus construct expressing human IL-10) delivery, but did not lead to increased or prolonged transgene expression when coexpressed with β-galactosidase. Expression of human IL-10 following AdV/hIL-10 instillation extended at least 14 days, was nonimmunogenic, and suppressed the development of neutralizing Abs against adenoviral proteins as well as against human IL-10. We conclude that TNF-α signaling through both the p55 and p75 receptor plays important roles in the clearance of adenoviral vectors and the magnitude of the humoral immune response. Additionally, although coexpression of human IL-10 with β- galactosidase had only modest effects on transgene expression, we demonstrate that AdV/hIL-10 is well tolerated, has extended expression compared with β- galactosidase, and is nonimmunogenic in the lung.

UR - http://www.scopus.com/inward/record.url?scp=18744436532&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=18744436532&partnerID=8YFLogxK

M3 - Article

VL - 164

SP - 443

EP - 451

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 1

ER -