Idd Loci Synergize to Prolong Islet Allograft Survival Induced by Costimulation Blockade in NOD Mice

  1. Julie Mangada1,2,
  2. Todd Pearson2,
  3. Michael A. Brehm3,
  4. Linda S. Wicker4,
  5. Laurence B. Peterson5,
  6. Leonard D. Shultz6,
  7. David V. Serreze6,
  8. Aldo A. Rossini2 and
  9. Dale L. Greiner (dale.greiner{at}umassmed.edu)2
  1. 1Program in Immunology and Virology
  2. 2Department of Medicine and
  3. 3Department of Pathology, at The University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655
  4. 4Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
  5. 5Department of Pharmacology, Merck Research Laboratories, Rahway, NJ 07065
  6. 6The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609

    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 virtually absent in NOD.B6/B10 Idd3 Idd5 mice. Islet allograft survival in NOD.B6 Idd3 mice treated with costimulation blockade is prolonged as compared to 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 × CBA)F1 mice treated with costimulation blockade was impaired as compared to similarly treated (C57BL/6.H2g7x CBA)F1 mice. Injection of exogenous 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 Idd loci can facilitate induction of transplantation tolerance by costimulation blockade and that IL-2/Idd3 is a critical component in this process.

    Footnotes

      • Received February 25, 2008.
      • Accepted October 17, 2008.

    This Article

    1. Published online before print November 4, 2008, doi: 10.2337/db08-0275
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