Combination Therapy With Epidermal Growth Factor and Gastrin Delays Autoimmune Diabetes Recurrence in Nonobese Diabetic Mice Transplanted With Syngeneic Islets

In a previous study, we observed that combination therapy of nonobese diabetic (NOD) mice with epidermal growth factor (EGF) and gastrin partially restored pancreatic islet β-cell mass and reversed hyperglycemia without the use of immunotherapy. Herein we have studied the effects of EGF plus gastrin on recurrent autoimmune responses in diabetic NOD mice transplanted with syngeneic islets. EGF (10 μg/kg) plus gastrin (30 μg/kg) given intraperitoneally (i.p.) once daily to diabetic NOD mice (blood glucose, 23 ± 2 mmol/L) significantly prolonged the median survival time of NOD islet grafts to 60 days (n = 10 mice) measured as the days until hyperglycemia recurrence (blood glucose ≥12 mmol/L; versus EGF alone to 36 days (n = 10), or gastrin alone, 19 days (n = 10), or vehicle, 11 days (n = 9). At 7-14 days after transplantation insulin-stained β-cells were much more numerous in islet grafts of EGF plus gastrin-treated mice (13.0 ± 0.9 × 105 cells) versus grafts in vehicle-treated mice (1.0 ± 0.3 × 105 cells). CD45+ leukocytes were significantly reduced in number and surrounded but did not destroy the β cells in the islets of EGF plus gastrin-treated mice (29 ± 2 × 105 cells) versus those in vehicle-treated mice (57 ± 3 × 105 cells). We concluded that the EGF plus gastrin combination therapy inhibited the recurrent autoimmune response and delayed rejection of syngeneic islet grafts, suggesting a therapeutic role for these peptides in islet transplantation.