Expression of adenoviral E3 transgenes in β cells prevents autoimmune diabetes

Matthias G. Von Herrath*, Shimon Efrat, Michael B.A. Oldstone, Marshall S. Horwitz

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

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 α (TNF-α). Because type I autoimmune diabetes destroys islets by mechanisms that involve class I MHC and TNF-α, 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 β 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 β 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 β-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-α cytolysis must await further genetic dissection of the introduced Ad genes.

Original languageEnglish
Pages (from-to)9808-9813
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number18
DOIs
StatePublished - 2 Sep 1997
Externally publishedYes

Funding

FundersFunder number
National Institute of Diabetes and Digestive and Kidney DiseasesR29DK051091
National Institute of Diabetes and Digestive and Kidney Diseases

    Keywords

    • Insulin-dependent diabetes mellitus
    • Lymphocytic choriomeningitis virus
    • Major histocompatibility complex expression

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