Protection of nonobese diabetic mice from autoimmune diabetes by reduction of islet mass before insulitis.

Abstract

Nonobese diabetic mice spontaneously develop diabetes that is caused by autoimmune cell-mediated destruction of pancreatic beta cells. Here we report that surgical removal of 90% of pancreatic tissue before onset of insulitis induced a long-term diabetes-free condition in nonobese diabetic mice. Pancreatectomy after development of moderate insulitis had no effect on the course of diabetes. The effect of pancreatectomy was abrogated with subsequent development of diabetes by infusion of islet-cell-specific T lymphocytes and by transplantation of pancreatic islets. Lymphocytes from pancreatectomized diabetes-free mice exhibited low response to islet cells but responded normally to alloantigens. These results suggest that the islet cell mass plays a critical role in development of autoimmune diabetes.Nonobese diabetic (NOD) mice spontaneously develop diabetes that has features similar to those of human insulindependent diabetes mellitus, a polygenic disease caused by autoimmune destruction of insulin-producing beta cells in the islets of Langerhans (1-3). The onset of this type of diabetes is preceded by a long period of insulitis that proceeds from lymphoid cell infiltration in the periphery of the islets (periinsulitis) to cellular infiltration invading the islets (insulitis) (4-8). Although a T lymphocyte-mediated autoimmune etiology is suggested in this model (9-16), the antigen(s) responsible for triggering the activation of autoreactive T lymphocytes has not been fully elucidated. Molecules localized in the islets that have been characterized as the candidate antigens include insulin (17), glutamic acid decarboxylase (18), glycolipids (19, 20), carboxypeptidase H (21), and cellular proteins with molecular masses of 38 kDa (22), 52 kDa (23), and 69 kDa (24).Regardless of the nature of islet autoantigen(s), initial activation of autoreactive T cells by the antigen(s) must take place sometime before the development of insulitis. Although it is likely that presentation of the autoantigen(s) to T cells occurs locally within the pancreas, there has been no study (to our knowledge) on whether the initiation of the diabetogenic process is a dose-dependent event in which a sufficient amount of islet antigen(s) in the pancreas must be presented to autoreactive T cells for activation. In this study, we examined whether reduction of overall islet mass by surgical removal of the pancreas has any influence in the subsequent development of diabetes in NOD mice. MATERIALS AND METHODSMice. Female NOD/MrkTacfBR mice were purchased from Taconic. In this strain of NOD mice, hyperglycemia is first observed when the mice are 14 weeks old, and the cumulative incidence of diabetes is 80% in females at 27 weeks (data provided by Taconic). Male C3H/He (H-2k) and DBA/1 (H-2q) mice (7-8 weeks old) were obtained from The Jackson Laboratory. All

Islet Mass Plays a Critical Role in Initiation, but not Progression, of the Diabetogenic Process in NOD Mice

“…Blood sugar levels remained within a normal range after pancreatectomy. Although the spleen was removed at the time of pancreatectomy for technical ease, splenectomy alone at 7 weeks of age had no protective effect with development of spontaneous diabetes in a similar manner as unmanipulated NOD mice [11].…”

“…Ninety percent pancreatectomy was performed at 7 weeks of age as previously described [11]. Approximately 10% (by weight and by insulin content) of the pancreas tissue was left intact adjacent to the second duodenal loop, with careful conservation of the common bile duct and major vessels surrounding the duodenum.…”

“…In our previous study, we demonstrated that surgical removal of 90% pancreatic tissue at an early age prior to the onset of insulitis induced a long-term diabetes-free condition in NOD mice [11]. Pancreatectomy after development of moderate insulitis had no protective effect, suggesting that the development of insulitis marks an important time point when the autoreactive T cell clone may become committed to differentiate into -celldestructive effector T cells.…”

New Potential Adjuncts to Treatment of Children With Type 1 Diabetes Mellitus

“…These parameters are difficult to assess in human subjects. There is evidence that experimentally induced changes in ␤-cell mass of nonobese diabetic mice early in the course of the autoimmune process can inhibit the subsequent development of disease (61). As T1DM is thought to result from progressive ␤-cell destruction and failure to regenerate ␤-cell mass, it remains possible that intervention with GLP-1R agonists will modify the natural course of ␤-cell destruction and/or regeneration, resulting in clinically detectable improvements in insulin secretion and glucose control.…”

Role of β-Cells in Type 1 Diabetes Pathogenesis

“…Altogether, these results confirm the role of islet antigens in the drive of the immune response. They also point to specific time windows for immune activation to proceed (64).…”