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

© 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details.

DOI of Published Version

10.2337/db08-0275

Source

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

Journal/Book/Conference Title

Diabetes

Related Resources

Link to Article in PubMed

PubMed ID

18984741

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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