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Transgenic Insulin (B:9-23) T-Cell Receptor Mice Develop Autoimmune Diabetes Dependent Upon RAG Genotype, H-2^g7 Homozygosity, and Insulin 2 Gene Knockout

¹ Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Aurora, Colorado
² Joslin Diabetes Center, Boston, Massachusetts

Address correspondence and reprint requests to Edwin Liu, Barbara Davis Center, P.O. Box 6511, MS B140, Aurora, CO 80045-6511. E-mail: edwin.liu{at}uchsc.edu

Abbreviations: FITC, fluorescein isothiocyanate; IFN, interferon; TCR, T-cell receptor

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 x NOD) and spontaneous diabetes in NOD.RAG^–/– (backcross 1 generation). Disease progression is heterogeneous and is modified by a series of genetic factors including heterozygosity (H-2^g7/H-2^q) versus homozygosity for H-2^g7, the presence of additional T-/B-cell receptor–rearranged genes (RAG⁺ versus RAG^–/–), and the insulin 2 gene knockout (the insulin gene expressed in the NOD thymus). Despite lymphopenia, 40% of H-2^g7/g7 BDC12-4.1 TCR⁺ RAG^–/– Ins2^–/– mice are diabetic by 10 weeks of age. As few as 13,500 transgenic T-cells from a diabetic TCR⁺ RAG^–/– 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.

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