Differential protection in transgenic lines of NOD/Lt mice hyperexpressing the autoantigen GAD65 in pancreatic β-cells

Margot Bridgett, Marina Cetkovic-Cvrlje, Robert O'Rourke, Yuguang Shi, Sandya Narayanswami, Jeremy Lambert, Vijayakumar Ramiya, Steinunn Baekkeskov, Edward H. Leiter

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Although expressed at very low levels in islets of NOD mice, GAD65 is a candidate islet autoantigen. Two transgenic lines of NOD/Lt mice expressing high levels of human GAD65 from a rat insulin promoter were generated. Transgenes were integrated on proximal chromosome 15 of the A line and on the Y chromosome of the Y line. Transgenic A-line mice were obligate hemizygotes, since homozygous expression resulted in developmental lethality. A twofold higher level of hGAD65 transcripts in A-line islets from young donors was associated with higher GAD protein and enzyme activity levels. Y-line males developed diabetes at a similar rate and incidence as standard NOD/Lt males. In contrast, A-line mice of both sexes exhibited a markedly lowered incidence of diabetes. Insulitis, present in both transgenic lines, developed more slowly in A-line mice and correlated with a reduction in the ratio of γ- interferon to interleukin-10 transcripts. Splenic leukocytes from young A- line donors transferred diabetes into NOD-scid recipients at a retarded rate compared with those from nontransgenic donors. Further, nontransgenic NOD T- cells transferred diabetes more slowly in NOD-scid recipients that were congenic for A-line transgenes as compared with standard NOD-scid recipients. Primed T-cell responses and spontaneous humoral reactivity to GAD65 failed to distinguish transgenic from nontransgenic mice. Quantitative differences in expression level or insertional mutagenesis are possible mechanisms of protection in the A line.

Original languageEnglish (US)
Pages (from-to)1848-1856
Number of pages9
JournalDiabetes
Volume47
Issue number12
DOIs
StatePublished - 1998
Externally publishedYes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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