Islet Expression of M3 Uncovers a Key Role for Chemokines in the Development and Recruitment of Diabetogenic Cells in NOD Mice

  1. Andrea P. Martin1,
  2. Marcos G. Grisotto1,
  3. Claudia Canasto-Chibuque1,
  4. Steven L. Kunkel2,
  5. Jonathan S. Bromberg134,
  6. Glaucia C. Furtado1 and
  7. Sergio A. Lira1
  1. 1Immunology Institute, Mount Sinai School of Medicine, New York, New York
  2. 2Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
  3. 3Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York
  4. 4Recanati/Miller Transplantation Institute, Mount Sinai School of Medicine, New York, New York
  1. Address correspondence and reprint requests to Dr. Sergio A. Lira, Immunology Institute, Mount Sinai School of Medicine, 1425 Madison Ave., Box 1630, New York, NY 10029-6574. E-mail: sergio.lira{at}mssm.edu

Abstract

OBJECTIVE—Type 1 diabetes is an autoimmune disease characterized by a local inflammatory reaction in and around islets followed by selective destruction of insulin-secreting β-cells. We tested the hypothesis that chemokines affect different mechanisms responsible for the development of diabetes in NOD mice.

RESEARCH DESIGN AND METHODS—We examined chemokine expression in islets of NOD mice and tested their functional relevance to development of diabetes using transgenic mice expressing the mouse herpesvirus 68–encoded chemokine decoy receptor M3 (NOD-M3 mice) in insulin-secreting β-cells.

RESULTS—Multiple chemokines were expressed in pancreatic islets of NOD mice before development of diabetes. Islet-specific expression of the pan-chemokine inhibitor M3 dramatically reduced leukocyte infiltration and islet destruction and completely blocked development of diabetes in NOD-M3 mice. M3 blocked diabetes by inhibiting the priming of diabetogenic cells in the pancreatic lymph nodes and their recruitment into the islets. This effect was specific to the pancreatic islets because M3 expression did not affect other ongoing autoimmune processes.

CONCLUSIONS—These results demonstrate that chemokines mediate afferent and efferent immunity in type 1 diabetes and suggest that broad chemokine blockade may represent a viable strategy to prevent insulitis and islet destruction.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 14 November 2007. DOI: 10.2337/db07-1309.

    Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-1309.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted November 5, 2007.
    • Received September 14, 2007.
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  1. Diabetes vol. 57 no. 2 387-394
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