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A series of recent studies in humans and the NOD mouse model have highlighted the central role that autoimmunity directed against insulin, in particular the insulin B chain 9-23 peptide, may play in the pathogenesis of type 1 diabetes. Both pathogenic and protective T-cell clones recognizing the B:9-23 peptide have been produced. This report describes the successful creation of BDC12-4.1 T-cell receptor (TCR) transgenic mice with spontaneous insulitis in F1 mice (FVB × NOD) and spontaneous diabetes in NOD.RAG^sup -/-^ (backcross 1 generation). Disease progression is heterogeneous and is modified by a series of genetic factors including heterozygosity (H-2^sup g7^/H-2^sup q^) versus homozygosity for H-2^sup g7^, the presence of additional T-/B-cell receptor-rearranged genes (RAG^sup +^ versus RAG^sup -/-^), and the insulin 2 gene knockout (the insulin gene expressed in the NOD thymus). Despite lymphopenia, 40% of H-2^sup g7/g7^ BDC12-4.1 TCR^sup +^ RAG^sup -/-^ Ins2^sup -/-^ mice are diabetic by 10 weeks of age. As few as 13,500 transgenic T-cells from a diabetic TCR^sup +^ RAG^sup -/-^ mouse can transfer diabetes to an NOD.scid mouse. The current study demonstrates that the BDC12-4.1 TCR is sufficient to cause diabetes at NOD backcross 1, bypassing polygenic inhibition of insulitis and diabetogenesis. Diabetes 55:1978-1984, 2006
In the NOD mouse model of type 1A diabetes, a series of islet molecules are targeted by humoral and/or cellular adaptive immune responses (1). We have been particularly interested in immune responses directed against insulin (2-5) with the hypothesis that amino acids 9-23 from the insulin B chain (B:9-23) may be a primary target of NOD anti-islet autoimmunity (6-9). Wegmann et al. (10) and Daniel et al. (11) cloned T-cells directly from islets of pre-diabetic NOD mice and reported that the majority of isolated CD4 clones react with insulin. More than 90% of such insulin-reactive clones specifically respond to insulin peptide B:9-23 (11). Furthermore, immunization with B:9-23 peptide or DNA sequences decreases diabetes in NOD mice (12,13), and the same peptide can induce insulin autoantibodies and diabetes in genetically engineered strains of mice (14,15). We have recent evidence that this I-A^sup g7^- and I-A^sup d^-restricted sequence (16,17) may be essential for the initiation of anti-islet autoimmunity of NOD mice with the observation that NOD mice with both proinsulin 1 and proinsulin 2 genes...