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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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NOD-mtALR mice are completely resistant to type 1 diabetes mediated by transfer of diabetogenic CD4+ T-cell clone BDC2.5. BDC2.5 T-cell clones were injected into NOD, NOD.mtALR, or ALR/LtJ mice. Development of diabetes after injection was monitored using Diastix, with a diagnosis of type 1 diabetes called after positive tests on 2 sequential days. AT, adoptive transfer.
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Figure 4: NOD-mtALR mice are completely resistant to type 1 diabetes mediated by transfer of diabetogenic CD4+ T-cell clone BDC2.5. BDC2.5 T-cell clones were injected into NOD, NOD.mtALR, or ALR/LtJ mice. Development of diabetes after injection was monitored using Diastix, with a diagnosis of type 1 diabetes called after positive tests on 2 sequential days. AT, adoptive transfer.

Mentions: The diabetogenic CD4+ T-cell clone BDC2.5 transferred diabetes to all NOD mice within 5 days (Fig. 4). In marked contrast to NOD mice, all ALR and NOD.mtALR mice remained diabetes free after transfer of BDC2.5 cells for the 28-day follow-up period. This confirms that when the T-effector population is limited to a single β-cell autoantigen a significant contribution to resistance can be demonstrated.


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)

NOD-mtALR mice are completely resistant to type 1 diabetes mediated by transfer of diabetogenic CD4+ T-cell clone BDC2.5. BDC2.5 T-cell clones were injected into NOD, NOD.mtALR, or ALR/LtJ mice. Development of diabetes after injection was monitored using Diastix, with a diagnosis of type 1 diabetes called after positive tests on 2 sequential days. AT, adoptive transfer.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 4: NOD-mtALR mice are completely resistant to type 1 diabetes mediated by transfer of diabetogenic CD4+ T-cell clone BDC2.5. BDC2.5 T-cell clones were injected into NOD, NOD.mtALR, or ALR/LtJ mice. Development of diabetes after injection was monitored using Diastix, with a diagnosis of type 1 diabetes called after positive tests on 2 sequential days. AT, adoptive transfer.
Mentions: The diabetogenic CD4+ T-cell clone BDC2.5 transferred diabetes to all NOD mice within 5 days (Fig. 4). In marked contrast to NOD mice, all ALR and NOD.mtALR mice remained diabetes free after transfer of BDC2.5 cells for the 28-day follow-up period. This confirms that when the T-effector population is limited to a single β-cell autoantigen a significant contribution to resistance can be demonstrated.

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