TRANSGENIC EXPRESSION OF IL-10 IN PANCREATIC-ISLET A-CELLS ACCELERATES AUTOIMMUNE INSULITIS AND DIABETES IN NONOBESE DIABETIC

To study the paracrine effect of IL-10 on autoimmune insulitis and dia betes, we produced IL-10 transgenic non-obese diabetic (NOD) mice (NOD -IL-10) in which murine IL-10 was expressed in pancreatic islet A cell s under the control of a rat glucagon promoter without directly manipu lating pancreatic islet B cells. Among 11 founder mice, four of four m ales and three of seven females developed diabetes by 10 weeks of age. Histological analysis of six NOD-IL-10 revealed severe insulitis and prominent ductal proliferation. NOD-IL-10 also showed spotty lymphocyt ic infiltration in the lung and liver in four of six founder mice. The onset of diabetes in NOD-IL-10 was remarkably earlier than that of 14 weeks of age at the earliest in female non-transgenic NOD mice. When the NOD-IL-10 mouse was backcrossed to C57BL/6 mice, none of the resul ting F-1, B-N-2 or B-N-3 generation toward C57BL/6 mice showed diabete s even at 39 weeks of age, in spite of the presence of peri-insulitis and prominent ductal proliferation, while two of four mice of the N-N- 2 generation toward NOD mice showed early-onset diabetes. Thus, transg enic paracrine expression of IL-10 in situ in the NOD genetic backgrou nd enhances autoimmune insulitis and diabetes in their onset and sever ity, ignoring gender difference. Because expression of IL-10 was detec ted by polymerase chain reaction in pancreatic islets of non-transgeni c NOD mice after 5 weeks of age, IL-10 secreted in situ is regarded to enhance cell-mediated autoimmune diabetes, in spite of established in vitro anti-T(h)1 activity of IL-10.