Idd loci synergize to prolong islet allograft survival induced by costimulation blockade in NOD mice.
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.


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.
Mangada
Julie
J
Program in Immunology and Virology, the University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Pearson
Todd
T
Brehm
Michael A
MA
Wicker
Linda S
LS
Peterson
Laurence B
LB
Shultz
Leonard D
LD
Serreze
David V
DV
Rossini
Aldo A
AA
Greiner
Dale L
DL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D023201:CD40 Ligand / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000601:surgery; D005434:Flow Cytometry; D006085:Graft Survival / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D007515:Islets of Langerhans / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000379:methods; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology; D051379:Mice; D020297:Mice, Congenic; D008809:Mice, Inbred C3H; D016688:Mice, Inbred NOD; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D023201:CD40 Ligand