NOD Congenic Mice Genetically Protected From Autoimmune Diabetes Remain Resistant to Transplantation Tolerance Induction
- Todd Pearson1,
- Thomas G. Markees2,
- Linda S. Wicker3,
- David V. Serreze124,
- Laurence B. Peterson5,
- John P. Mordes2,
- Aldo A. Rossini126 and
- Dale L. Greiner12
- 1Program in Immunology and Virology, the University of Massachusetts Medical School, Worcester, Massachusetts
- 2Department of Medicine, the University of Massachusetts Medical School, Worcester, Massachusetts
- 3Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, University of Cambridge, Cambridge, U.K
- 4The Jackson Laboratory, Bar Harbor, Maine
- 5Department of Pharmacology, Merck Research Laboratories, Rahway, New Jersey
- 6Department of Molecular Medicine, the University of Massachusetts Medical School, Worcester, Massachusetts
Abstract
The loss of self-tolerance leading to autoimmune type 1 diabetes in the NOD mouse model involves at least 19 genetic loci. In addition to their genetic defects in self-tolerance, NOD mice resist peripheral transplantation tolerance induced by costimulation blockade using donor-specific transfusion and anti-CD154 antibody. Hypothesizing that these two abnormalities might be related, we investigated whether they could be uncoupled through a genetic approach. Diabetes-resistant NOD and C57BL/6 stocks congenic for various reciprocally introduced Idd loci were assessed for their ability to be tolerized. Surprisingly, in NOD congenic mice that are almost completely protected from diabetes, costimulation blockade failed to prolong skin allograft survival. In reciprocal C57BL/6 congenic mice with NOD-derived Idd loci, skin allograft survival was readily prolonged by costimulation blockade. These data indicate that single or multiple combinations of evaluated Idd loci that dramatically reduce diabetes frequency do not correct resistance to peripheral transplantation tolerance induced by costimulation blockade. We suggest that mechanisms controlling autoimmunity and transplantation tolerance in NOD mice are not completely overlapping and are potentially distinct, or that the genetic threshold for normalizing the transplantation tolerance defect is higher than that for preventing autoimmune diabetes.
Footnotes
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Address correspondence and reprint requests to Dale L. Greiner, Diabetes Division, University of Massachusetts Medical School, Two Biotech, Suite 218, 373 Plantation St., Worcester, MA 01605. E-mail: dale.greiner{at}umassmed.edu.
Received for publication 6 May 2002 and accepted in revised form 29 October 2002.
L.S.W. owns stock in Merck.
ELISA, enzyme-linked immunosorbent assay; mAb, monoclonal antibody; DST, donor-specific transfusion; MHC, major histocompatibility complex; MST, median survival time; NK, natural killer.
The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.
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