Effect of the expression of DR alpha E beta NOD molecule on the development of insulitis and diabetes in the non-obese diabetic (NOD) mouse.

Abstract

Previous studies have shown that a transgenic I-E alpha gene, the mouse homologue of human DR alpha gene, prevents the development of insulitis and hence of diabetes in NOD mice. To investigate the mechanism of this prevention, we generated two strains of NOD mice expressing DR alpha E beta molecule: DR alpha-24-NOD expressing DR alpha E beta molecule on thymic epithelial cells (TEC) and bone marrow-derived cells (BDC), and DR alpha-30-NOD expressing DR alpha E beta molecule only on the TEC, and these mice were monitored for disease development. Because the DR alpha E beta molecule reconstituted I-E controlled immune regulation, it would become clear which cell type, TEC or BDC, was responsible for the I-E-mediated disease protection. To our surprise, however, DR alpha-24-NOD developed insulitis and diabetes comparably to non-transgenic littermates. This suggested that the difference in structure between DR alpha and E alpha molecules contributed to the difference in preventive effect on the development of insulitis and diabetes between DR alpha-24-NOD and E alpha-NOD. In an analysis of the T cell proliferative responses to glutamic acid decarboxylase (GAD) 65-derived peptides which were known to be diabetogenic autoantigens, it was shown that DR alpha-24-NOD and NOD acquired comparable level of T cell response to GAD 509-528 but 5-10-fold higher response was observed in E alpha-NOD. This suggested that I-ANOD and E alpha E beta NOD molecules could present GAD 509-528 peptide to T cells, while DR alpha E beta NOD could not. Furthermore, T cells from DR alpha transgenic mice showed proliferative response to antigen-presenting cells from E alpha transgenic mice in primary mixed lymphocyte reaction. This also suggested that the E alpha E beta molecule does differ in structure and peptide binding from the DR alpha E beta molecule. Present data suggested a possibility that the T cell repertoire selection, or the T cell response to GAD 65 and/or other unknown antigens specifically mediated by I-E molecule, may contribute to the prevention of disease development in E alpha-NOD.