Very-low-dose streptozotocin induces diabetes in insulin promoter-mB7-1 transgenic mice.
Transgenic mice that express mouse B7-1 (mB7-1, recently designated CD80) on their pancreatic beta-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 beta-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 beta-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 insulin-dependent diabetes models.
Harlan
D M
DM
Immune Cell Biology Program, Naval Medical Research Institute, Bethesda, Maryland 20889-5607, USA.
Barnett
M A
MA
Abe
R
R
Pechhold
K
K
Patterson
N B
NB
Gray
G S
GS
June
C H
CH
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D018122:B7-1 Antigen / Q000096:biosynthesis* / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D004198:Disease Susceptibility; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006029:Glycosuria; D007328:Insulin / Q000032:analysis / Q000235:genetics*; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology*; D008212:Lymphocyte Depletion; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D013311:Streptozocin / Q000008:administration & dosage / Q000633:toxicity*; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors
D000906:Antibodies; D018122:B7-1 Antigen; D001786:Blood Glucose; D007328:Insulin; D013311:Streptozocin