Program in Immunology and Virology; Department of Medicine, Division of Diabetes; Department of Pathology
Animals; Antibodies, Monoclonal; CD40 Ligand; Cytotoxicity, Immunologic; Diabetes Mellitus, Type 1; Flow Cytometry; Graft Survival; Islets of Langerhans; Islets of Langerhans Transplantation; Killer Cells, Natural; Mice; Mice, Congenic; Mice, Inbred C3H; Mice, Inbred NOD; Transplantation, Homologous
Life Sciences | Medicine and Health Sciences
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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DOI of Published Version
Diabetes. 2009 Jan;58(1):165-73. Epub 2008 Nov 4. Link to article on publisher's site
Mangada, Julie A.; Pearson, Todd; Brehm, Michael A.; Wicker, Linda S.; Peterson, Laurence B.; Shultz, Leonard D.; Serreze, David V.; Rossini, Aldo A.; and Greiner, Dale L., "Idd loci synergize to prolong islet allograft survival induced by costimulation blockade in NOD mice" (2008). Open Access Articles. 1985.
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