FIG. 1.

Administration of high doses of IL-2 to NOD mice: toxicity and diabetes development. A: Male and female NOD mice 5 weeks of age (top) or 12–14 weeks of age (middle and bottom) were injected daily with PBS (●, females; ○, males), 250,000 IU IL-2 (■, females; □, males), or 500,000 IU IL-2 (▲, females; △, males) over 20 days. Shown are Kaplan-Meier survival curves of treated mice (top and middle) and the percentage of diabetes-free mice; *P < 0.05 (Gehan-Breslow-Wilcoxon test) (bottom). B and C: Male and female NOD mice 12–14 weeks of age were injected for 5 days with PBS (●, females; ○, males,) or 250,000 IU IL-2 (■, females; □, males) and analyzed 2 h after the last injection. B: Wet weight of lungs (left), liver (middle), and CNS (right) was determined. Symbols represent individual mice and horizontal lines represent the median. **P < 0.01 (unpaired, two-tailed Student t test). C: Histological quantification of islet infiltration by immune cells in female and male NOD mice. Shown are the percentages of islets with no infiltration (0), peri-insulitis (1), moderate insulitis with <50% islet area infiltrated by immune cells (2), and severe insulitis with more than 50% islet area infiltrated by immune cells (3). Pictures show representative islets corresponding to the insulitis score used for analysis. D: Prediabetic female NOD mice 12–16 weeks of age were fasted for 4 h and injected with PBS or 250,000 IU IL-2 followed by a glucose bolus 2 h later. Results are presented as blood glucose levels during the 4-h follow-up (left) and as area under the blood–glucose curve (AUC) during the follow-up period (right), symbols represent individual mice, and horizontal lines represent the median. Data are cumulative of two (A, top) to five (A, middle and bottom) independent experiments or are representative of one (B and C) to three (D) independent experiments. ns, not significant.