mt-Nd2~a Modifies Resistance Against Autoimmune Type 1 Diabetes in NOD Mice at the Level of the Pancreatic β-Cell

摘要

Objective-to investigate whether a single nucleotide polymorphism (snp) in the mitochondrial gene for nadh dehydro-genase 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-nd2~a allele (nod.mt/~(alr)) were created and compared with standard nod (carrying the mt-nd2~c 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.mt~(alr) (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-nd2~a 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-nd2~a 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. Diabetes 60:355-359, 2011