Genetic Control of Diabetes Induction by Complete Freund's Adjuvant Combined with Subdiabetogenic Doses of Streptozotocin in Lewis Rats - Evidence for Transient Cytotoxicity against Beta Cells

Summary

The non-specific activation of the immune system by administration of complete Freund's adjuvant (CFA) was examined in two congenic Lewis rat strains LEW. 1A (RTl^a) and LEW. 1W (RT1^u) as a possible mean of amplification of the specific immune response, directed to pancreatic beta cells induced by multiple non-diabetogenic injections of streptozotocin (STZ). Rats were given intraperitoneally 0.5 ml CFA and 1 day later 25 mg/kg body weight STZ. This combined treatment was repeated twice at weekly intervals. Control groups received vehicle, STZ or CFA only with the same doses and at the same times. Only CFA/STZ-treated rats developed a persisting hyper-glycaemia (>15 mmol/1 glucose) namely 3/18 (17%) LEW. 1W and 47/76 (62%) LEW. 1A rats. The pancreatic insulin content in these hyperglycaemic rats was reduced by 96.6% in LEW. 1A rats and by 93% in LEW. 1W rats measured 8 weeks after the last CFA/STZ treatment. The response to CFA indicated by an increase of number of peripheral leucocytes and relative spleen weight gain at 7 days after CFA administration, was higher in LEW. 1A rats compared with those of LEW. 1W rats. Spleen cells harvested 72 h/48 h after the first and second CFA/STZ administration showed a cytotoxic reaction to isolated syngeneic islets as measured by ⁵¹Cr-release in vitro. Control rats receiving vehicle, STZ or CFA only showed no cellular anti-islet cytotoxicity. The anti-islet cytotoxicity of spleen cells was only transient and disappeared after the third CFA/STZ administration. Anti-islet cytotoxic antibodies were not detectable in this short-term study. The present study indicates the pathogenic potential of polyclonal lymphocyte activation by CFA for the autoimmune killing of pancreatic beta cells induced by STZ-modified antigens. The susceptibility to CFA/STZ induced pancreatic beta cell damage was influenced by the major histocompatibility complex of the rat. The CFA/STZ administration seems to lead to a transient break in immune tolerance for beta cells.

Key words

Anti-islet cytotoxicity - Experimental diabetes - Genetic control - Streptozotocin - Freund's adjuvant - Lewis rats