355회 The role of GAD in the pathogenesis of Type I diabetes

355회

연사 :  임 혜 원, 강원대학교 생명과학연구소

제목: The role of GAD in the pathogenesis of Type I diabetes

Abstract

Insulin-dependent diabetes mellitus results from the cell-mediated autoimmune destruction of insulin producing pancreatic beta-cells. The involvement of a variety of beta-cell antigens has been reported in humans and NOD mice. Among them, glutamic acid decarboxylase (GAD) appears to play a critical role in the initiation and development of diseases.  In the present study, the H-AS-GAD mouse in which GAD expression was suppressed was used to develop transgenic mice for the investigation of the role of GAD in the pathogenesis of IDDM. First, H-AS-GAD mice were continuously backcrossed with NOD mice for 12 generations to obtain an NOD genotype. Diabetes did not occur in H-AS-GAD mice in any generation. Second, to investigate the effect of the suppression of GAD expression on the fully established diabetogenic splenocytes derived from acutely diabetic NOD mice, H-AS-GAD SCID mice were produced by backcrossing H-AS-GAD mice with NOD SCID mice. Diabetogenic splenocytes did not transfer disease into H-AS-GAD SCID mice, while transgene-negative SCID mice became diabetic within 4 weeks after adoptive transfer. Finally, the significance of GAD was examined in a Super-GAD65 transgenic mouse carrying a sense-GAD65 transgene under the control of the MHC class I promoter for systemic expression of GAD65. To suppress GAD expression in the Super-GAD65 transgenic mouse in a beta-cell-specific manner, H-AS-GAD mice were mated with Super-GAD65 mice and the incidence of diabetes was monitored in Double-transgenic mice expressing both sense GAD65 and anti-sense GAD65/67 transgenes. None of the Double transgenic mice in which GAD expression was suppressed developed diabetes. However, approximately 80% of transgene-negative mice developed diabetes. Thus, beta cell-specific GAD expression is necessary for the development of IDDM and GAD-related autoimmunity may be involved in the pathogenic disease process.