Destruction of pancreatic beta cells in rats by complete Freund's adjuvant combined with non-diabetogenic doses of streptozotocin.
Non-specific activation of the immune system by complete Freund's adjuvant (CFA) in combination with non-diabetogenic doses of streptozotocin (STZ) was used to study autoimmune reactions against pancreatic islets. Male Lewis RT1a rats received either CFA (0.5 ml/kg) 24 hr prior to the injection of STZ (25 mg/kg), or CFA or STZ alone. The injections of CFA followed by STZ, but not CFA or STZ alone, produced a 69% (p less than 0.01) reduction in pancreatic insulin content associated with necrosis and a decrease of the relative volume density of insulin-immunoreactive cells without affecting other islet cells. Two injections of CFA and STZ induced hyperglycemia. This was associated with a depletion of pancreatic insulin and a significant reduction in the relative volume density of insulin-immunoreactive cells (p less than 0.01) and in the mean islet area (p less than 0.01). On day 20, after treatment with 3 injections of CFA and STZ, the animals developed persistent hyperglycemia. The pancreata in these rats contained less than 12% B-cells, and the insulin content was reduced by 96% (p less than 0.01). The main components of the remaining atrophic islets were glucagon- and somatostatin-immunoreactive cells. No significant lymphocytic infiltration into the islets was detectable, but the exocrine parenchyma exhibited severe inflammatory lesions. Degranulation and vacuolation of B-cells was evident by ultra-structural analysis. The volume densities of insulin containing cells and islet area were not changed after 3 injections of either CFA or STZ alone, although the pancreatic insulin content decreased by 61% (p less than 0.01) and 39% (p less than 0.05), respectively. These treatments did not produce an increase in plasma glucose. The present results demonstrate that CFA in combination with non-diabetogenic doses of the beta cytotoxic agent STZ induces B-cell destruction without significant insulitis. Our observations support the hypothesis that activation of the immune system by CFA allows an anti-B-cell immune reaction to develop following exposure to STZ.
D000818:Animals; D005620:Freund's Adjuvant / Q000494:pharmacology*; D006651:Histocytochemistry; D006943:Hyperglycemia / Q000209:etiology* / Q000276:immunology; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008213:Lymphocyte Activation; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D013311:Streptozocin / Q000494:pharmacology*
D007328:Insulin; D013311:Streptozocin; D005620:Freund's Adjuvant