Immunostimulation by complete Freund's adjuvant, granulocyte macrophage colony‐stimulating factor, or interferon‐γ reduces severity of diabetic embryopathy in ICR mice

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Abstract
BACKGROUND Increased risk of fetal malformation is a complication occurring in pregnant women with type 1 diabetes. Local (uterine) immune stimulation has been shown to reduce diabetes-induced teratogenesis in mice. Limited information is available regarding the ability of diverse methods of maternal immune stimulation to cause this effect or regarding timing requirements of the immune stimulation. METHODS Diabetes was induced in pregnant ICR mice by streptozocin (STZ) injection. Three different techniques of maternal immune stimulation, complete Freund's adjuvant (CFA), granulocyte-macrophage colony-stimulating factor (GM-CSF), or interferon-γ (IFN-γ), were then used to stimulate the immune system of the mice. RESULTS Approximately 50% of fetuses from hyperglycemic (>26 mM/liter blood glucose) dams were malformed, with neural tube defects predominating. Maternal immune stimulation during the time of normoglycemia, i.e., prior to the onset of hyperglycemia, was necessary to reduce teratogenic effects associated with hyperglycemia for each of the immune stimulants. The immune-stimulated diabetic mice then produced significantly lower and approximately equal numbers of malformed fetuses: CFA 20.9%, GM-CSF 23.3%, and IFN-γ 13.9%. CONCLUSIONS These results suggest that mechanistically diverse forms of nonspecific immune activation result in protection against diabetes-related teratogenesis, but only if given prior to onset of hyperglycemia. Birth Defects Research (Part A) 67:000–000, 2003.