Complement‐dependent antibody‐mediated cytotoxicity in the spontaneously diabetic BB/OK rat: association with β cell volume density

The present study examined in the spontaneously diabetic BB/OK rat whether a relationship exists between the appearance of complement-dependent antibody-mediated cytotoxicity (C'AMC) in serum and the relative β cell volume density determined in pancreatic biopsies. C'AMC was estimated by 51Cr release from prelabeled major histocompatibility complex-compatible neonatal rat islet cells afterexposure to rat serum and rabbit complement. Fifty-one percent (72/141) of sera from BB/OK rats with newly diagnosed diabetes were positive for C'AMC. At onset of hyperglycemia, insulin-immunoreactive β cells were only detectable in pancreas biopsies of 25% (10/40) of the BB/OK rats who displayed mild hyperglycemia(plasma glucose 8.3—13.0 mmol/l) and low serum C'AMC. A twofold increase (p < 0.01) of C'AMC and loss of the remaining β cells was evident in untreated animals upon their reexamination within 1 week after diagnosis of hyperglycemia. Initiation of insulin therapy prevented neither the increase in C'AMC activity nor the decrease in the β cell volume density. In contrast, three out of four mildly hyperglycemic BB/OK rats treated with cyclosporin A maintained both their initial C'AMC levels and relative β cell volume density not only throughout the treatment period (4 weeks) but also for at least 4 weeks thereafter. In one additional animal receiving cyclosporin A no protection of the remaining β cells could be achieved and C'AMC levels were markedly increased. It is concluded that the appearance of increased C'AMC in serum may reflect autoimmune reactions against the islet β cells of spontaneously diabetic BB/OK rats. Theincrease of C'AMC seen in untreated as well as insulin-treated BB/OK rats, whichwere even devoid of β cells, suggests that C'AMC activity appears secondary to the loss of β cells. These results do not support the hypothesis of a direct β cell destruction via intrainsular complement activation.