title: Adenovirus early region 3 antiapoptotic 10.4K, 14.5K, and 14.7K genes decrease the incidence of autoimmune diabetes in NOD mice.
abstract: Genes in the early region 3 (E3) of the adenovirus genome allow the virus to evade host immune responses by interfering with major histocompatibility (MHC) class I-mediated antigen presentation and tumor necrosis factor-alpha (TNF-alpha)- or Fas-induced apoptosis of infected cells. Autoimmune type 1 diabetes (T1D) is inhibited in NOD mice transgenically expressing all E3 genes under control of a rat insulin promoter (RIPE3/NOD). For dissecting the protective mechanisms afforded by various E3 genes, they were subdivided into RIP-driven transgene constructs. Strong T1D protection mediated at the beta-cell level characterized DL704/NOD mice lacking the E3 gp19K gene suppressing MHC class I expression but retaining the 10.4K, 14.5K, and 14.7K genes inhibiting Fas- or TNF-alpha-induced apoptosis and TNF-alpha-induced NF-kB activation. Much weaker protection characterized DL309/NOD mice expressing the gp19K but not the 10.4K, 14.5K, and 14.7K genes. While RIPE3/NOD splenocytes had an unexpected decrease in ability to adoptively transfer T1D, splenocytes from both the DL704 and DL309 stocks efficiently did so. These findings indicate that all E3 genes must be expressed to inhibit the diabetogenic potential of NOD immune cells. They also demonstrate that the antiapoptotic E3 genes most effectively protect pancreatic beta-cells from diabetogenic immune responses.
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Pierce
authors.forename: Harold D
authors.initials: HD
authors.lastname: Chapman
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Post
authors.forename: Anton
authors.initials: A
authors.lastname: Svetlanov
authors.forename: Shimon
authors.initials: S
authors.lastname: Efrat
authors.forename: Marshall
authors.initials: M
authors.lastname: Horwitz
authors.forename: David V
authors.initials: DV
authors.lastname: Serreze
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000517:prevention & control* / Q000821:virology*; D005260:Female; D016679:Genome, Viral; D007328:Insulin / Q000235:genetics; D008285:Major Histocompatibility Complex; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008970:Molecular Weight; D011401:Promoter Regions, Genetic; D051381:Rats; D014764:Viral Proteins / Q000235:genetics
chemical_list: D007328:Insulin; D014764:Viral Proteins