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Susceptibility to IDDM is strongly associated with major histocompatibility complex (MHC) class II genotypes. Nonobese diabetic (NOD) mice develop a similar autoimmune diabetes and have a unique MHC class II IA allele that is required for the development of diabetes. A number of groups have shown that the introduction of resistant MHC class II alleles as transgenes into the NOD mouse protects from diabetes. We made control transgenic NOD mice, expressing their own IAbeta^sup g7^ molecule as a transgene. One of two lines of these mice showed a reduced incidence of diabetes, without any change in T-cell proliferative response to a number of diabetes autoantigens or any change in insulitis severity. This line developed a subtle decrease in the percentage of splenic B-cells that progressed with age. This defect was not associated with any other phenotypic abnormalities. Our findings suggest that assessment of splenic B-cell number is necessary in interpretation of the effects of MHC class II transgenes on the development of diabetes in the NOD mouse. Diabetes 46:1970-1974,1997
The NOD mouse develops autoimmune diabetes and provides a good model of human type 1 diabetes. Genetic analyses have demonstrated linkage of susceptibility to the major histocompatibility complex (MHC) (1). The first external domain of the I-AD chain in the NOD MHC is unique, with histidine and serine at positions 56 and 57, instead of the proline and aspartic acid found in other strains (2). In humans, the presence or absence of aspartic acid at position 57 is associated with resistance or susceptibility, respectively, to diabetes (3). Residue 57 plays an important role in peptide binding to MHC class II, as it points into the peptide binding groove, and, when it is an aspartic acid residue, can form a salt bridge with a conserved arginine residue at position 76 on the alpha-chain (4). To define the role of the MHC in diabetes, transgenic mice expressing resistant I-A or mutated NOD I-A[g7 molecules were developed (5-9). These transgenic mice are protected from diabetes. Because a number of lines of MHC class II transgenic mice generated in our laboratory have demonstrated a range of abnormalities, including loss of mature B-cells (10), we made control transgenic NOD mice expressing their own I-AP[7 molecule. In this study, we describe...