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Transgenic insulin (B:9-23) T-cell receptor mice develop autoimmune diabetes dependent upon RAG genotype, H-2g7 homozygosity, and insulin 2 gene knockout.

Diabetes | Jul 28, 2006

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.

Pubmed ID: 16804066 RIS Download

Mesh terms: Adoptive Transfer | Animals | CD4-Positive T-Lymphocytes | CD8-Positive T-Lymphocytes | Crosses, Genetic | Diabetes Mellitus | Diabetes Mellitus, Type 1 | Female | Genes, RAG-1 | Heterozygote | Insulin | Interferon-gamma | Male | Mice | Mice, Inbred NOD | Mice, Knockout | Mice, Transgenic | Receptors, Antigen, T-Cell

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Associated grants

  • Agency: NIAID NIH HHS, Id: AI50864
  • Agency: NIDDK NIH HHS, Id: DK064605
  • Agency: NIDDK NIH HHS, Id: DK32083
  • Agency: NIDDK NIH HHS, Id: DK55969
  • Agency: NIDDK NIH HHS, Id: DK62718
  • Agency: NIDDK NIH HHS, Id: P30 DK57516

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