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 JA, Pearson T, Brehm MA, Wicker LS, Peterson LB, Shultz LD, Serreze DV, Rossini AA, Greiner DL. (2008). Idd loci synergize to prolong islet allograft survival induced by costimulation blockade in NOD mice. Open Access Articles. https://doi.org/10.2337/db08-0275. Retrieved from https://escholarship.umassmed.edu/oapubs/1985
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