Differential protection in two transgenic lines of NOD/Lt mice hyperexpressing the autoantigen GAD65 in pancreatic beta-cells
| Autor: | Vijayakumar K. Ramiya, Margot Bridgett, Robert W. O'Rourke, Marina Cetkovic-Cvrlje, Steinunn Baekkeskov, Jeremy Lambert, Edward H. Leiter, Yuguang Shi, Sandya Narayanswami |
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| Rok vydání: | 1998 |
| Předmět: |
Male
medicine.medical_specialty Adoptive cell transfer Ratón Insulin Antibodies Endocrinology Diabetes and Metabolism Transgene Gene Dosage Congenic Gene Expression Mice Transgenic Mice SCID Weaning Nod Biology Autoantigens Islets of Langerhans Mice Mice Inbred NOD Internal medicine Internal Medicine medicine Animals Transgenes Autoantibodies NOD mice geography Binding Sites geography.geographical_feature_category Glutamate Decarboxylase Reverse Transcriptase Polymerase Chain Reaction Incidence Pancreatic Diseases medicine.disease Islet Adoptive Transfer Diabetes Mellitus Type 1 Endocrinology Genes Cytokines Female Insulitis |
| Zdroj: | Diabetes. 47:1848-1856 |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | 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 gamma-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. |
| Databáze: | OpenAIRE |
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