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Idd loci synergize to prolong islet allograft survival induced by costimulation blockade in NOD mice.

Mangada J, Pearson T, Brehm MA, Wicker LS, Peterson LB, Shultz LD, Serreze DV, Rossini AA, Greiner DL - Diabetes (2008)

Bottom Line: Conversely, some Idd loci were not beneficial for the induction of transplantation tolerance.Injection of exogenous interleukin (IL)-2 into NOD mice treated with costimulation prolonged islet allograft survival.These data suggest that Idd loci can facilitate induction of transplantation tolerance by costimulation blockade and that IL-2/Idd3 is a critical component in this process.

View Article: PubMed Central - PubMed

Affiliation: Program in Immunology and Virology, the University of Massachusetts Medical School, Worcester, Massachusetts, USA.

ABSTRACT

Objective: NOD mice model human type 1 diabetes and are used to investigate tolerance induction protocols for islet transplantation in a setting of autoimmunity. However, costimulation blockade-based tolerance protocols have failed in prolonging islet allograft survival in NOD mice.

Research design and methods: To investigate the underlying mechanisms, we studied the ability of costimulation blockade to prolong islet allograft survival in congenic NOD mice bearing insulin-dependent diabetes (Idd) loci that reduce the frequency of diabetes.

Results: The frequency of diabetes is reduced in NOD.B6 Idd3 mice and is virtually absent in NOD.B6/B10 Idd3 Idd5 mice. Islet allograft survival in NOD.B6 Idd3 mice treated with costimulation blockade is prolonged compared with NOD mice, and in NOD.B6/B10 Idd3 Idd5, mice islet allograft survival is similar to that achieved in C57BL/6 mice. Conversely, some Idd loci were not beneficial for the induction of transplantation tolerance. Alloreactive CD8 T-cell depletion in (NOD x CBA)F1 mice treated with costimulation blockade was impaired compared with similarly treated (C57BL/6.H2(g7) x CBA)F1 mice. Injection of exogenous interleukin (IL)-2 into NOD mice treated with costimulation prolonged islet allograft survival. NOD.B6 Idd3 mice treated with costimulation blockade deleted alloreactive CD8 T-cells and exhibited prolonged islet allograft survival.

Conclusions: Il2 is the Idd3 diabetes susceptibility gene and can influence the outcome of T-cell deletion and islet allograft survival in mice treated with costimulation blockade. These data suggest that Idd loci can facilitate induction of transplantation tolerance by costimulation blockade and that IL-2/Idd3 is a critical component in this process.

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Scatter plot of alloreactive CD8+ T-cell deletion in synchimeric mice. (KB5 CBA × C57BL/6.H2g7)F1 mice and (KB5 CBA × NOD)F1 synchimeric mice were treated with a C57BL/6 DST on day −7 and anti-CD154 mAb on days −7 and −4 relative to analysis of their circulating levels of KB5 transgenic CD8+ T-cells on day 0 as described in research design and methods. P values are indicated by horizontal bars.
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f4: Scatter plot of alloreactive CD8+ T-cell deletion in synchimeric mice. (KB5 CBA × C57BL/6.H2g7)F1 mice and (KB5 CBA × NOD)F1 synchimeric mice were treated with a C57BL/6 DST on day −7 and anti-CD154 mAb on days −7 and −4 relative to analysis of their circulating levels of KB5 transgenic CD8+ T-cells on day 0 as described in research design and methods. P values are indicated by horizontal bars.

Mentions: (KB5 CBA × C57BL/6.H2g7)F1 synchimeric mice treated with costimulation blockade exhibited marked deletion of their alloreactive CD8+ T-cells (63 ± 30%, Fig. 4). Similar results were seen in the (KB5 CBA × C57BL/6.H2g7)F1 synchimeric mice that received exogenous IL-2 in addition to the DST and anti-CD154 (70 ± 6%). In contrast, (KB5 CBA × NOD)F1 mice exhibited significantly less deletion of their alloreactive CD8+ T-cell population (34 ± 24%), which was restored by IL-2 treatment (63 ± 21%) to a level similar to that observed in (KB5 CBA × C57BL/6.H2g7)F1 mice (Fig. 4).


Idd loci synergize to prolong islet allograft survival induced by costimulation blockade in NOD mice.

Mangada J, Pearson T, Brehm MA, Wicker LS, Peterson LB, Shultz LD, Serreze DV, Rossini AA, Greiner DL - Diabetes (2008)

Scatter plot of alloreactive CD8+ T-cell deletion in synchimeric mice. (KB5 CBA × C57BL/6.H2g7)F1 mice and (KB5 CBA × NOD)F1 synchimeric mice were treated with a C57BL/6 DST on day −7 and anti-CD154 mAb on days −7 and −4 relative to analysis of their circulating levels of KB5 transgenic CD8+ T-cells on day 0 as described in research design and methods. P values are indicated by horizontal bars.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2606867&req=5

f4: Scatter plot of alloreactive CD8+ T-cell deletion in synchimeric mice. (KB5 CBA × C57BL/6.H2g7)F1 mice and (KB5 CBA × NOD)F1 synchimeric mice were treated with a C57BL/6 DST on day −7 and anti-CD154 mAb on days −7 and −4 relative to analysis of their circulating levels of KB5 transgenic CD8+ T-cells on day 0 as described in research design and methods. P values are indicated by horizontal bars.
Mentions: (KB5 CBA × C57BL/6.H2g7)F1 synchimeric mice treated with costimulation blockade exhibited marked deletion of their alloreactive CD8+ T-cells (63 ± 30%, Fig. 4). Similar results were seen in the (KB5 CBA × C57BL/6.H2g7)F1 synchimeric mice that received exogenous IL-2 in addition to the DST and anti-CD154 (70 ± 6%). In contrast, (KB5 CBA × NOD)F1 mice exhibited significantly less deletion of their alloreactive CD8+ T-cell population (34 ± 24%), which was restored by IL-2 treatment (63 ± 21%) to a level similar to that observed in (KB5 CBA × C57BL/6.H2g7)F1 mice (Fig. 4).

Bottom Line: Conversely, some Idd loci were not beneficial for the induction of transplantation tolerance.Injection of exogenous interleukin (IL)-2 into NOD mice treated with costimulation prolonged islet allograft survival.These data suggest that Idd loci can facilitate induction of transplantation tolerance by costimulation blockade and that IL-2/Idd3 is a critical component in this process.

View Article: PubMed Central - PubMed

Affiliation: Program in Immunology and Virology, the University of Massachusetts Medical School, Worcester, Massachusetts, USA.

ABSTRACT

Objective: NOD mice model human type 1 diabetes and are used to investigate tolerance induction protocols for islet transplantation in a setting of autoimmunity. However, costimulation blockade-based tolerance protocols have failed in prolonging islet allograft survival in NOD mice.

Research design and methods: To investigate the underlying mechanisms, we studied the ability of costimulation blockade to prolong islet allograft survival in congenic NOD mice bearing insulin-dependent diabetes (Idd) loci that reduce the frequency of diabetes.

Results: The frequency of diabetes is reduced in NOD.B6 Idd3 mice and is virtually absent in NOD.B6/B10 Idd3 Idd5 mice. Islet allograft survival in NOD.B6 Idd3 mice treated with costimulation blockade is prolonged compared with NOD mice, and in NOD.B6/B10 Idd3 Idd5, mice islet allograft survival is similar to that achieved in C57BL/6 mice. Conversely, some Idd loci were not beneficial for the induction of transplantation tolerance. Alloreactive CD8 T-cell depletion in (NOD x CBA)F1 mice treated with costimulation blockade was impaired compared with similarly treated (C57BL/6.H2(g7) x CBA)F1 mice. Injection of exogenous interleukin (IL)-2 into NOD mice treated with costimulation prolonged islet allograft survival. NOD.B6 Idd3 mice treated with costimulation blockade deleted alloreactive CD8 T-cells and exhibited prolonged islet allograft survival.

Conclusions: Il2 is the Idd3 diabetes susceptibility gene and can influence the outcome of T-cell deletion and islet allograft survival in mice treated with costimulation blockade. These data suggest that Idd loci can facilitate induction of transplantation tolerance by costimulation blockade and that IL-2/Idd3 is a critical component in this process.

Show MeSH
Related in: MedlinePlus