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

  1. Julie Mangada12,
  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. Greiner2
  1. 1Program in Immunology and Virology, the University of Massachusetts Medical School, Worcester, Massachusetts
  2. 2Department of Medicine, the University of Massachusetts Medical School, Worcester, Massachusetts
  3. 3Department of Pathology, the University of Massachusetts Medical School, Worcester, Massachusetts
  4. 4Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K
  5. 5Department of Pharmacology, Merck Research Laboratories, Rahway, New Jersey
  6. 6The Jackson Laboratory, Bar Harbor, Maine
  1. Corresponding author: Dale L. Greiner, dale.greiner{at}umassmed.edu

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 × CBA)F1 mice treated with costimulation blockade was impaired compared with similarly treated (C57BL/6.H2g7 × 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.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 4 November 2008.

  • The contents of this study are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.

  • Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted October 17, 2008.
    • Received February 25, 2008.
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  1. Published online before print November 4, 2008, doi: 10.2337/db08-0275 Diabetes January 2009 vol. 58 no. 1 165-173
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