Islet Allograft Survival Induced by Costimulation Blockade in NOD Mice Is Controlled by Allelic Variants of Idd3

  1. Todd Pearson1,
  2. Peter Weiser2,
  3. Thomas G. Markees2,
  4. David V. Serreze123,
  5. Linda S. Wicker4,
  6. Laurence B. Peterson5,
  7. Anne-Marie Cumisky5,
  8. Leonard D. Shultz123,
  9. John P. Mordes2,
  10. Aldo A. Rossini126 and
  11. Dale L. Greiner12
  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. 3The Jackson Laboratory, Bar Harbor, Maine
  4. 4Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, University of Cambridge, Cambridge, U.K
  5. 5Department of Pharmacology, Merck Research Laboratories, Rahway, New Jersey
  6. 6Program in Molecular Medicine, The University of Massachusetts Medical School, Worcester, Massachusetts
  1. Address correspondence and reprint requests to Dale L. Greiner, PhD, University of Massachusetts Medical School, 373 Plantation St., Biotech 2, Suite 218, Worcester, MA 01605. E-mail: dale.greiner{at}umassmed.edu

Abstract

NOD mice develop type 1 autoimmune diabetes and exhibit genetically dominant resistance to transplantation tolerance induction. These two phenotypes are genetically separable. Costimulation blockade fails to prolong skin allograft survival in (NOD × C57BL/6)F1 mice and in NOD-related strains made diabetes-resistant by congenic introduction of protective major histocompatibility complex (MHC) or non-MHC Idd region genes. Here, we tested the hypothesis that the genetic basis for the resistance of NOD mice to skin allograft tolerance also applies to islet allografts. Surprisingly, costimulation blockade induced permanent islet allograft survival in (NOD × C57BL/6)F1 mice but not in NOD mice. After costimulation blockade, islet allograft survival was prolonged in diabetes-resistant NOD.B6 Idd3 mice and shortened in diabetes-free C57BL/6 mice congenic for the NOD Idd3 variant. Islet allograft tolerance could not be induced in diabetes-resistant NOD.B10 Idd5 and NOD.B10 Idd9 mice. The data demonstrate that 1) NOD mice resist islet allograft tolerance induction; 2) unlike skin allografts, resistance to islet allograft tolerance is a genetically recessive trait; 3) an Idd3 region gene(s) is an important determinant of islet allograft tolerance induction; and 4) there may be overlap in the mechanism by which the Idd3 resistance locus improves self-tolerance and the induction of allotolerance.

Footnotes

  • T.P. and P.W. contributed equally to this work.

    • Accepted April 29, 2004.
    • Received December 26, 2003.
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  1. doi: 10.2337/diabetes.53.8.1972 Diabetes August 2004 vol. 53 no. 8 1972-1978
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