INSULITIS AND ISLET-CELL ANTIBODY-FORMATION IN RATS WITH EXPERIMENTALLY REDUCED BETA-CELL MASS

We studied the effect of severe reduction of beta-cell mass by 90% pan createctomy On the immune tolerance to the endocrine pancreas. Four mo nths after subtotal pancreatectomy all LEW.Han rats had developed mono nuclear infiltration of islets and 9 of 14 rats were positive for isle t-cell antibodies. Electron microscopy revealed lymphocytic invasion o f endocrine tissue, lysis of beta cells and phagocytotic macrophages. None of these changes were seen 2 weeks after 90% pancreatectomy or 4 months after 10% pancreatectomy. Weekly substitution of islet antigens in the form of a homogenate of 100 islets into 90% pancreatectomized LEW.Han rats almost completely prevented the development of insulitis and autoantibodies. The dependence of insulitis on T cells was shown w hen 90% pancreatectomy in LEW.rnu rats (i.e., the congenic athymic nud e strain), did not result in islet infiltration. The exocrine tissue r emained normal in all experimental groups. During the observation peri od insulitis was not associated with overt diabetes but was accompanie d by substantial enlargement of islets and of beta-cell mass, as shown by morphometry. Suppression of islet inflammation by injection of isl et antigens abolished beta-cell regeneration, despite continuing metab olic stress in rats with 90% pancreatectomy. The findings indicate ind uction of islet autoimmunity in response to 90% but not to 10% pancrea tectomy. We conclude that severe reduction of the islet-antigen mass a llows the development of T-cell-dependent islet autoimmunity which ind icates a loss of immune tolerance. In addition, the data suggest the e xistence of islet-antigen autoreactive immune cells in rats not geneti cally predisposed to autoimmune diabetes. Finally, we conclude that se lective beta-cell regeneration occurs in association with insulitis.