Growth of Neonatal Islet Transplants in the Spontaneously Diabetic BB/Wor Rat

We have previously shown that culture-isolated neonatal islets are able to survive both rejection and the recurrence of autoimmunity in the spontaneously diabetic BB/Wor rat. In trials designed to demonstrate the MHC restriction of the autoimmune response in this model, we discovered that neonatal islet graftsfrom diabetic BB rats appeared larger than grafts from nondiabetic controls. This study was undertaken to quantify the mass difference seen in this original study and to determine the characteristics of graft growth in more highly controlled trials. Grafts from diabetic animals in the original study were significantly larger than those from nondiabetic animals (81 ± 36 vs. 238 ± 216 μg, P = 0.01). These findings were supported by results from a second series of experiments, in which the mean growth index of grafts from diabetic animals was 7.25 ± 4.91, whereas that from nondiabetic animals was 2.5 ± 1.15 (P = 0.011). Three animals in this study were reversed of hyperglycemia: two had normal and one had a subdiabetic ip GTTs. These three rats received 97, 317, and 408 ng of islet tissue that increased in mass to 1790, 3270, and 4107 fig, respectively. Nuclear/total cell area percentages were the same in diabetic and nondiabetic grafts (P = 0.76), suggesting that the increase in mass was attributable primarily to proliferation rather than hypertrophy. Limited studies that use BrDU incorporation support this conclusion. High glucose levels have been shown to stimulate β-cell replication in fetal, neonatal, and adult islets and may be the stimulus for enhanced graft growth in this model. This study shows that small, immunomodulated neonatal grafts placed in the diabetic environment of the spontaneously diabetic BB/Wor rat can increase in mass >10-fold and can ameliorate the symptoms of diabetes.