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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

Reciprocal adoptive transfers (ATs) were performed into immunodeficient NOD-Rag1 females expressing either mt-Nd2 allele as recipients and splenic leukocytes from diabetic NOD or diabetic conplastic donors (NOD.mtALR). Splenocytes from these donor mice were collected and erythrocytes removed using hypotonic solution treatment. Cells were injected intravenously (tail vein) at 2 × 107 cells/mouse into age-matched female recipients. The source of the mitochondrial population in either diabetic donor splenocytes or in Rag1 recipients did not significantly affect rate of diabetes development in NOD recipients.
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Figure 2: Reciprocal adoptive transfers (ATs) were performed into immunodeficient NOD-Rag1 females expressing either mt-Nd2 allele as recipients and splenic leukocytes from diabetic NOD or diabetic conplastic donors (NOD.mtALR). Splenocytes from these donor mice were collected and erythrocytes removed using hypotonic solution treatment. Cells were injected intravenously (tail vein) at 2 × 107 cells/mouse into age-matched female recipients. The source of the mitochondrial population in either diabetic donor splenocytes or in Rag1 recipients did not significantly affect rate of diabetes development in NOD recipients.

Mentions: To identify effects of mt-Nd2a on immune functions versus an effect on pancreatic β-cells, reciprocal adoptive transfers were performed. Donors were either diabetic NOD females or diabetic NOD.mtALR females. All recipients were age-matched immunodeficient Rag1−/− females separately expressing each mt-Nd2 allotype. Neither allotype expressed by mitochondria in splenocytes from diabetic donors significantly affected adoptive transfer (Fig. 2). Similarly, the mt-Nd2 allotype expressed by the recipients had no significant effect on the adoptive transfer kinetics regardless of the allotype expressed by the transferred leukocytes. Thus, in the absence of other ALR-protective nuclear genes, the ALR-derived mt-Nd2a allele cannot deviate the attack mediated by the plethora of autoreactive T-cells present in spleens of diabetic donors.


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)

Reciprocal adoptive transfers (ATs) were performed into immunodeficient NOD-Rag1 females expressing either mt-Nd2 allele as recipients and splenic leukocytes from diabetic NOD or diabetic conplastic donors (NOD.mtALR). Splenocytes from these donor mice were collected and erythrocytes removed using hypotonic solution treatment. Cells were injected intravenously (tail vein) at 2 × 107 cells/mouse into age-matched female recipients. The source of the mitochondrial population in either diabetic donor splenocytes or in Rag1 recipients did not significantly affect rate of diabetes development in NOD recipients.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 2: Reciprocal adoptive transfers (ATs) were performed into immunodeficient NOD-Rag1 females expressing either mt-Nd2 allele as recipients and splenic leukocytes from diabetic NOD or diabetic conplastic donors (NOD.mtALR). Splenocytes from these donor mice were collected and erythrocytes removed using hypotonic solution treatment. Cells were injected intravenously (tail vein) at 2 × 107 cells/mouse into age-matched female recipients. The source of the mitochondrial population in either diabetic donor splenocytes or in Rag1 recipients did not significantly affect rate of diabetes development in NOD recipients.
Mentions: To identify effects of mt-Nd2a on immune functions versus an effect on pancreatic β-cells, reciprocal adoptive transfers were performed. Donors were either diabetic NOD females or diabetic NOD.mtALR females. All recipients were age-matched immunodeficient Rag1−/− females separately expressing each mt-Nd2 allotype. Neither allotype expressed by mitochondria in splenocytes from diabetic donors significantly affected adoptive transfer (Fig. 2). Similarly, the mt-Nd2 allotype expressed by the recipients had no significant effect on the adoptive transfer kinetics regardless of the allotype expressed by the transferred leukocytes. Thus, in the absence of other ALR-protective nuclear genes, the ALR-derived mt-Nd2a allele cannot deviate the attack mediated by the plethora of autoreactive T-cells present in spleens of diabetic donors.

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