Title

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

UMMS Affiliation

Program in Immunology and Virology; Department of Medicine, Division of Diabetes; Department of Pathology

Publication Date

11-6-2008

Document Type

Article

Subjects

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

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

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.

Rights and Permissions

Citation: Diabetes. 2009 Jan;58(1):165-73. Epub 2008 Nov 4. Link to article on publisher's site

DOI of Published Version

10.2337/db08-0275

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Diabetes

PubMed ID

18984741