Scripps VIVO scripps research logo

  • Index
  • Log in
  • Home
  • People
  • Organizations
  • Research
  • Events
Search form

Expression of adenoviral e3 transgenes in beta cells prevents autoimmune diabetes

Academic Article
uri icon
  • Overview
  • Research
  • Identity
  • Additional Document Info
  • View All
scroll to property group menus

Overview

authors

  • VonHerrath, M. G.
  • Efrat, S.
  • Oldstone, Michael
  • Horwitz, M. S.

publication date

  • September 1997

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • The adenovirus (Ad) genome contains immunoregulatory and cytokine inhibitory genes that are presumed to function in facilitating acute infection or in establishing persistence in vivo. Some of these genes are clustered in early region 3 (E3), which contains a 19-kDa glycoprotein (gp19) that inhibits the transport of selected class I major histocompatibility complex (MHC) molecules out of the endoplasmic reticulum. In addition, the E3 region contains three protein inhibitors of the cytolytic function of tumor necrosis factor alpha (TNF-alpha). Because type I autoimmune diabetes destroys islets by mechanisms that involve class I MHC and TNF-alpha, we investigated whether the entire cassette of Ad E3 genes might prevent the onset of diabetes in a well studied lymphocytic choriomeningitis viral (LCMV) murine model of virus-induced autoimmune diabetes. In this model, a LCMV polypeptide (either glycoprotein or nucleoprotein) expressed as a transgene in the islets is a target for autoimmune destruction of beta cells after LCMV infection. In this scenario the LCMV-induced immune response is directed not only against the virus but also against the LCMV transgenes expressed in the beta cells. Our experiments demonstrated a very efficient prevention of this LCMV-triggered diabetes by the Ad E3 genes. This resulted from the inhibition of target cell recognition by a fully competent and LCMV-primed immune system. Unlike the results from the beta-2 microglobulin gene deletion experiments, our approach shows that selective regulation at the level of the target cell is sufficient to prevent autoimmune diabetes without disrupting the function of the systemic immune response. Although the Ad genes in these experiments were provided as transgenes, recent experiments may permit the introduction of such genes through the use of viral vectors. Although the decrease in class I MHC in islets by Ad genes was demonstrated in these in vivo studies, the relative importance of this process and the control of TNF-alpha cytolysis must await further genetic dissection of the introduced Ad genes.

subject areas

  • Adenoviridae
  • Adenovirus E3 Proteins
  • Animals
  • Diabetes Mellitus, Type 1
  • Gene Expression
  • Gene Expression Regulation
  • Gene Transfer Techniques
  • Major Histocompatibility Complex
  • Mice
  • Mice, Transgenic
scroll to property group menus

Research

keywords

  • insulin-dependent diabetes mellitus
  • lymphocytic choriomeningitis virus
  • major histocompatability complex expression
scroll to property group menus

Identity

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.94.18.9808

PubMed ID

  • 9275207
scroll to property group menus

Additional Document Info

start page

  • 9808

end page

  • 9813

volume

  • 94

issue

  • 18

©2021 The Scripps Research Institute | Terms of Use | Powered by VIVO

  • About
  • Contact Us
  • Support