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mt-Nd2(a) Modifies resistance against autoimmune type 1 diabetes in NOD mice at the level of the pancreatic β-cell.

Chen J, Gusdon AM, Piganelli J, Leiter EH, Mathews CE - Diabetes (2010)

Bottom Line: NIT-4 cells with mt-Nd2(a) were also more resistant to AI4-mediated destruction in vitro than NIT-1 cells.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, USA.

ABSTRACT

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-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.

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Related in: MedlinePlus

There is no significant difference in spontaneous type 1 diabetes incidence in either female (A) or male (B) NOD mice (mt-Nd2c allele) compared with NOD.mtALR conplastic mice with the ALR-derived mt-Nd2a allele. Incidence studies were performed independently at The Jackson Laboratory and The Children's Hospital of Pittsburgh using both female and male NOD and NOD.mtALR conplastic mice. These two studies obtained equivalent incidence results, and the combined analysis is presented.
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Figure 1: There is no significant difference in spontaneous type 1 diabetes incidence in either female (A) or male (B) NOD mice (mt-Nd2c allele) compared with NOD.mtALR conplastic mice with the ALR-derived mt-Nd2a allele. Incidence studies were performed independently at The Jackson Laboratory and The Children's Hospital of Pittsburgh using both female and male NOD and NOD.mtALR conplastic mice. These two studies obtained equivalent incidence results, and the combined analysis is presented.

Mentions: Comparable rates of type 1 diabetes incidence were recorded for NOD and NOD.mtALR (Fig. 1). Although there was a trend toward slower incidence in male NOD.mtALR, the difference was not significant. A study of insulitis development in female NOD and NOD.mtALR mice from 4 to 16 weeks of age was also performed. Consistent with diabetes incidence, there were no differences in the histological scores comparing age-matched NOD with NOD.mtALR mice (data not shown).


mt-Nd2(a) Modifies resistance against autoimmune type 1 diabetes in NOD mice at the level of the pancreatic β-cell.

Chen J, Gusdon AM, Piganelli J, Leiter EH, Mathews CE - Diabetes (2010)

There is no significant difference in spontaneous type 1 diabetes incidence in either female (A) or male (B) NOD mice (mt-Nd2c allele) compared with NOD.mtALR conplastic mice with the ALR-derived mt-Nd2a allele. Incidence studies were performed independently at The Jackson Laboratory and The Children's Hospital of Pittsburgh using both female and male NOD and NOD.mtALR conplastic mice. These two studies obtained equivalent incidence results, and the combined analysis is presented.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3012193&req=5

Figure 1: There is no significant difference in spontaneous type 1 diabetes incidence in either female (A) or male (B) NOD mice (mt-Nd2c allele) compared with NOD.mtALR conplastic mice with the ALR-derived mt-Nd2a allele. Incidence studies were performed independently at The Jackson Laboratory and The Children's Hospital of Pittsburgh using both female and male NOD and NOD.mtALR conplastic mice. These two studies obtained equivalent incidence results, and the combined analysis is presented.
Mentions: Comparable rates of type 1 diabetes incidence were recorded for NOD and NOD.mtALR (Fig. 1). Although there was a trend toward slower incidence in male NOD.mtALR, the difference was not significant. A study of insulitis development in female NOD and NOD.mtALR mice from 4 to 16 weeks of age was also performed. Consistent with diabetes incidence, there were no differences in the histological scores comparing age-matched NOD with NOD.mtALR mice (data not shown).

Bottom Line: NIT-4 cells with mt-Nd2(a) were also more resistant to AI4-mediated destruction in vitro than NIT-1 cells.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, USA.

ABSTRACT

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-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.

Show MeSH
Related in: MedlinePlus