Transgenic mice that express mouse B7-1 (mB7-1, recently designated CD80) on their pancreatic β-cells maintain normal islet architecture, have normal pancreatic insulin content, and only rarely spontaneously develop insulitis and diabetes. Nevertheless, these mice display an extreme sensitivity to streptozotocin (STZ)-induced diabetes. Female mice were administered two STZ doses intraperitoneally, 20 and 40 mg/kg body wt, each for five consecutive days. Nontransgenic but otherwise syngeneic mice responded to the STZ with a moderate diminution in pancreatic insulin content but not with persistent glycosuria. In striking contrast, STZ administered to transgenic mice resulted in a severe diminution of pancreatic insulin content and in diabetes. Notably, the lower STZ dose resulted in diabetes only after a prolonged (26- to 100-day) latency. STZ-induced diabetes appears to be T-cell dependent, since treatment with T-cell–depleting (and in particular CD8+ subset-depleting) antibodies ameliorated the response. Anti-mB7-1 monoclonal antibody administration also prevented STZ-induced diabetes. Thus, unmasked mB7-1 is a required component in the pathway resulting in β-cell killing. Immunohistological analysis revealed that early after STZ administration, both mB7-1 transgenic and nontransgenic mice developed insulitis. While this insulitis resolved in the nontransgenic mice, the islet-infiltrating CD4+ and CD8+ T-cells in the transgenic mice were associated with complete β-cell destruction. These data suggest that STZ-induced diabetes in mB7-1 transgenic mice is an immune-mediated process with distinct potential advantages over existing insulindependent diabetes models.
Very-Low-Dose Streptozotocin Induces Diabetes in Insulin Promoter-mB7-1 Transgenic Mice
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David M Harlan, Michelle A Barnett, Ryo Abe, Klaus Pechhold, Noelle B Patterson, Gary S Gray, Carl H June; Very-Low-Dose Streptozotocin Induces Diabetes in Insulin Promoter-mB7-1 Transgenic Mice. Diabetes 1 July 1995; 44 (7): 816–823. https://doi.org/10.2337/diab.44.7.816
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