OBJECTIVE To investigate whether a single nucleotide polymorphism (SNP) in the mitochondrial gene for NADH dehydrogenase 2 (mt-Nd2) can modulate susceptibility to type 1 diabetes in NOD mice.
RESEARCH DESIGN AND METHODS NOD/ShiLtJ mice conplastic for the alloxan resistant (ALR)/Lt-derived mt-Nd2a allele (NOD.mtALR) were created and compared with standard NOD (carrying the mt-Nd2c allele) for susceptibility to spontaneous autoimmune diabetes, or to diabetes elicited by reciprocal adoptive splenic leukocyte transfers, as well as by adoptive transfer of diabetogenic T-cell clones. β-Cell lines derived from either the NOD (NIT-1) or the NOD.mtALR (NIT-4) were also created to compare their susceptibility to cytolysis by diabetogenic CD8+ T-cells in vitro.
RESULTS NOD mice differing at this single SNP developed spontaneous or adoptively transferred diabetes at comparable rates and percentages. However, conplastic mice with the mt-Nd2a allele exhibited resistance to transfer of diabetes by the CD4+ T-cell clone BDC 2.5 as well as the CD8+ AI4 T-cell clones from T-cell receptor transgenic animals. NIT-4 cells with mt-Nd2a were also more resistant to AI4-mediated destruction in vitro than NIT-1 cells.
CONCLUSIONS Conplastic introduction into NOD mice of a variant mt-Nd2 allele alone was not sufficient to prevent spontaneous autoimmune diabetes. Subtle nonhematopoietic type 1 diabetes resistance was observed during adoptive transfer experiments with T-cell clones. This study confirms that genetic polymorphisms in mitochondria can modulate β-cell sensitivity to autoimmune T-cell effectors.
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- Received September 2, 2010.
- Accepted October 12, 2010.
- © 2011 by the American Diabetes Association.
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