Inhibition of tumor necrosis factor alpha by an adenovirus-encoded soluble fusion protein extends transgene expression in the liver and lung. Academic Article uri icon

Overview

MeSH

  • Animals
  • Antibodies, Viral
  • Antigens, CD
  • Antigens, CD8
  • Antigens, CD95
  • Enzyme-Linked Immunosorbent Assay
  • Genetic Therapy
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, SCID
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I

MeSH Major

  • Adenoviridae
  • Liver
  • Lung
  • Recombinant Fusion Proteins
  • Transgenes
  • Tumor Necrosis Factor-alpha

abstract

  • The cellular and humoral immune responses to adenovirus (Ad) remain a major barrier to Ad-mediated gene therapy. We recently reported that mice deficient in tumor necrosis factor alpha (TNF-alpha) or Fas (APO-1, CD95) have prolonged expression of an Ad transgene expressing a foreign protein in the liver. To determine whether blockade of TNF-alpha or Fas would have the same effect in normal mice, we created transgenes that expressed soluble murine CD8 or CD8 fused to the extracellular regions of TNF receptor 1 (TNFR) or Fas and inserted into the left-end region of first-generation (E1/E3-) Ad vectors. Consistent with the results observed in TNF-deficient mice, expression of the TNFR-CD8 fusion protein was prolonged in vivo compared to that of control proteins. Not only did expression of TNFR-CD8 persist in the liver and the lung, but when coadministered with another first-generation vector, the protein provided "transprotection" for the companion vector and transgene. In addition, TNFR-CD8 attenuated the humoral immune response to the Ad. Together, these findings demonstrate that blockade of TNF-alpha is likely to be useful in extending the expression of an Ad-encoded transgene in a gene therapy application.

publication date

  • June 1999

has subject area

  • Adenoviridae
  • Animals
  • Antibodies, Viral
  • Antigens, CD
  • Antigens, CD8
  • Antigens, CD95
  • Enzyme-Linked Immunosorbent Assay
  • Genetic Therapy
  • Liver
  • Lung
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, SCID
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Recombinant Fusion Proteins
  • Transgenes
  • Tumor Necrosis Factor-alpha

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC112555

PubMed ID

  • 10233973

Additional Document Info

start page

  • 5098

end page

  • 5109

volume

  • 73

number

  • 6