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Previous studies have shown that a transgenic I-Eα gene, the mouse homologue of human DRα 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 DRαEβ molecule: DRα-24-NOD expressing DRαEβ molecule on thymic epithelial cells (TEC) and bone marrow-derived cells (BDC), and DRα -30-NOD expressing DRα Eβ molecule only on the TEC, and these mice were monitored for disease development. Because the DRαEβ 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, DRα -24-NOD developed insulitis and diabetes comparably to non-transgenic littermates. This suggested that the difference in structure between DRα and Eα molecules contributed to the difference in preventive effect on the development of insulitis and diabetes between DRα-24-NOD and Eα-NOD. In an analysis of the T cell proliferative responses to glutamic acid decarboxylase (GAD) 65-derived peptides which were known lo be diabetogenic autoantigens, it was shown that DRα-24-NOD and NOD acquired comparable level of T cell response to GAD 509-528 but 5-10-fold higher response was observed in Eα-NOD. This suggested that I-ANOD and EαEβNOD molecules could present GAD 509-528 peptide to T cells, while DRαEβNOD could not. Furthermore, T cells from DRα transgenic mice showed proliferative response to antigen-presenting cells from Eα transgenic mice in primary mixed lymphocyte reaction. This also suggested that the Eα Eβ molecule does differ in structure and peptide binding from the DRαEβ 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 Eα-NOD. [ABSTRACT FROM AUTHOR]

Immune responsiveness of 121 patients with post-schistosomal liver cirrhosis to schistosomal antigens was investigated. Out of 78 patients, only five (6.4%) showed low responsiveness to schistosomal adult worm antigen whereas 73 (93.6%) were high responders. Out of 57 healthy individuals with previous schistosomal infection, low responders were found in 17.5%. The frequency of low responders to schistosomal adult worm antigen was significantly decreased in the patients with post-schistosomal liver cirrhosis (P < 005). Out of 121 patients, a significant increase in frequency of HLA-Bw44- DEn haplotype was observed (corrected P < 0.02). On the other hand, HLA- Bw52-Dw 12 haplotype which was reported to be in strong linkage disequilibrium with an immune suppression gene for schistosomal adult worm antigen was significantly decreased (corrected P < 0.005). These observations suggested that an HLA-linked immune suppression gene controlled susceptibility or resistance to post-schistosomal liver cirrhosis through regulation of immune responsiveness of the hosts to schistosomal antigen in man. [ABSTRACT FROM AUTHOR]