DIFFERENTIAL PROTECTION IN 2 TRANSGENIC LINES OF NOD LT MICE HYPEREXPRESSING THE AUTOANTIGEN GAD65 IN PANCREATIC BETA-CELLS/

Although expressed at very low levels in islets of NOD mice, GAD65 is a candidate islet autoantigen. Two transgenic Lines of NOD/Lt mice exp ressing high levels of human GAD65 from a rat insulin promoter mere ge nerated. Transgenes were integrated on proximal chromosome 15 of the A line and on the Y chromosome of the Y line. Transgenic A-line mice we re obligate hemizygotes, since homozygous expression resulted in devel opmental lethality. A twofold higher level of hGAD65 transcripts in A- line islets from young donors was associated with higher GAD protein a nd enzyme activity levels. Y-line males developed diabetes at a simila r rate and incidence as standard NOD/Lt males. In contrast, A-Line mic e of both sexes exhibited a markedly lowered incidence of diabetes. In sulitis, present in both transgenic lines, developed more slowly in A- Line mice and correlated with a reduction in the ratio of gamma-interf eron to interleukin-10 transcripts. Splenic leukocytes from young Alin e donors transferred diabetes into NOD-scid recipients at a retarded r ate compared with those from nontransgenic donors. Further, nontransge nic NOD T-cells transferred diabetes more slowly in NOD-scid recipient s that were congenic for A-line transgenes as compared with standard N OD-scid recipients. Primed T-cell responses and spontaneous humoral re activity to GAD65 failed to distinguish transgenic from nontransgenic mice. Quantitative differences in expression level or insertional muta genesis are possible mechanisms of protection in the A line.